Compounds and compositions for the treatment of parasitic disease

ABSTRACT

The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application No. 61/224,433, filed 9 Jul. 2009. The full disclosure of this application is incorporated herein by reference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.

2. Background

Malaria is an infectious disease caused by four protozoan parasites: Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world and over the last few decades the malaria burden has steadily increased. An estimated 1-3 million people die every year from malaria—mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives.

Leishmaniasis is caused by one or more than 20 varieties of parasitic protozoa that belong to the genus Leishmania, and is transmitted by the bite of female sand flies. Leishmaniasis is endemic in about 88 countries, including many tropical and sub-tropical areas.

There are four main forms of Leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form and is caused by the parasite Leishmania donovani. Patients who develop visceral leishmaniasis can die within months unless they receive treatment. The two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®). Sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem. In addition, the treatment is relatively long and painful, and can cause undesirable side effects.

Human African Trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. The parasites concerned are protozoa belonging to the Trypanosoma Genus. They are transmitted to humans by tsetse fly (Glossina Genus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites.

Chagas disease (also called American Trypanosomiasis) is another human parasitic disease that is endemic amongst poor populations on the American continent. The disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking insects. The human disease occurs in two stages: the acute stage, which occurs shortly after infection and the chronic stage, which can develop over many years. Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle and sometimes dilation of the digestive tract, as well as weight loss. Untreated, the chronic disease is often fatal.

The drugs currently available for treating Chagas disease are Nifurtimox and benznidazole. However, problems with these current therapies include their diverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Furthermore, treatment is really only effective when given during the acute stage of the disease. Resistance to the two frontline drugs has already occurred. The antifungal agent Amphotericin b has been proposed as a second-line drug, but this drug is costly and relatively toxic.

In view of the foregoing, it is desirable to develop novel compounds as antiparasitic agents.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound selected from Formula Ia, Ib and Ic:

in which:

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1, 2, 3 and 4;

R_(a) is selected from hydrogen, halo, —X₃NR₇R₈, —X₃OR₈, —X₃S(O)₀₋₂R₈, —X₃C(O)NR₇R₈, —X₃R₈, benzyl and C₆₋₁₀aryl optionally substituted with 1 to 3 radicals independently selected from halo, C₁₋₄alkyl, halo-substituted-C₁₋₄alkyl, C₁₋₄alkoxy and halo-substituted-C₁₋₄alkoxy; wherein X₃ is selected from a bond and C₁₋₄alkylene;

R_(b) is selected from hydrogen and C₁₋₄alkyl;

R₁ is selected from halo, —OR₁₃, —C(O)OR₁₃, —NR₁₃R₁₄, C₆₋₁₀aryl and a saturated, unsaturated or partially unsaturated 4-9 member heterocyclic ring containing up to three nitrogens; wherein R₁₃ is selected from hydrogen, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl, C₃₋₈cycloalkyl-C₀₋₄alkyl, —X₁NHC(O)R₁₅, —X₁C(NH)NHR₁₅, —X₁C(O)NHR₁₅, —X₁NHR₁₅, —X₁OR₁₅, —C(O)R₁₅ and —C(O)OR₁₅; wherein X₁ is selected from a bond and C₁₋₄alkylene; R₁₅ is selected from hydrogen, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl and benzyl; and R₁₄ is selected from hydrogen, C₁₋₆alkyl and hydroxy-substituted-C₁₋₆alkyl; wherein any aryl or heterocyclic of R₁ is optionally substituted with 1-3 radicals independently selected from halo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, C₁₋₆alkoxy and halo-substituted-C₁₋₆alkoxy;

or R₁₃ and R₁₄ together with the nitrogen to which R₁₃ and R₁₄ are attached form a saturated, unsaturated or partially unsaturated 5-9 member heterocyclic ring containing up to three heteroatoms selected from N, NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said heterocyclic ring formed by the combination of R₁₃ and R₁₄ is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, C₁₋₆alkyl, amino-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkyl;

R₂ is selected from hydrogen, C₁₋₆alkyl, amino, C₃₋₈cycloalkyl-C₀₋₄alkyl, C₆₋₁₀aryl-C₀₋₄alkyl, halo-substituted-C₁₋₆alky, hydroxy-substituted-C₁₋₆alkyl and heterocyclyl-C₀₋₄alkyl; wherein said heterocyclyl is a saturated, unsaturated or partially unsaturated 5-9 member heterocyclic ring containing up to three heteroatoms selected from N, NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said C₆₋₁₀aryl or heterocyclic of R₂ is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, —NHR₁₇, —(CH₂)₀₋₂NHC(O)R₁₇, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, amino-substituted-C₁₋₆alkyl and C₁₋₆alkoxy; wherein R₁₇ is selected from hydrogen and C₁₋₆alkyl;

R₃ is selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl, —X₂C(O)OR₁₆, —X₂S(O)₀₋₂R₁₆, —X₂OR₁₆, —X₂C(O)NHR₁₆ and —X₂NHC(O)R₁₆; wherein X₂ is selected from a bond and C₁₋₄alkylene; and R₁₆ is selected from hydrogen, C₁₋₆alkyl and C₆₋₁₀aryl-C₀₋₄alkyl; wherein said aryl of R₁₆ is optionally substituted with 1 to 3 radicals independently selected from halo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, C₁₋₆alkoxy and halo-substituted-C₁₋₆alkoxy;

or R₂ and R₃ together with the carbon atom to which R₂ and R₃ are attached forms C₃₋₈cycloalkyl;

or R₂ and R₁₃ together with the atoms to which R₂ and R₁₃ are attached form a ring selected from C₃₋₈cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said heterocyclic form the combination of R₂ and R₁₃ is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, C₁₋₆alkyl and halo-substituted-C₁₋₆alkyl;

R₄ is selected from hydrogen and C₁₋₆alkyl;

R₅ is selected from hydrogen and C₁₋₆alkyl; or R₄ and R₅ together with the carbon atom to which R₄ and R₅ are attached forms C₃₋₈cycloalkyl;

R₆ is selected from C₆₋₁₀aryl, C₃₋₈cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said aryl or heterocyclic of R₆ is optionally substituted by 1 to 3 radicals independently selected from halo, hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy;

R₇ is selected from hydrogen and C₁₋₃alkyl;

R₈ is selected from C₁₋₁₀alkyl (straight or branched), C₆₋₁₀aryl-C₀₋₄alkyl, C₃₋₈cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said aryl or heterocyclic of R₈ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, hydroxy, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, C₁₋₆alkoxy, —C(O)OR₁₈, —S(O)₀₋₂R₁₈, —C(O)NHR₁₈, —NHS(O)₀₋₂R₁₈, phenyl and a saturated, unsaturated or partially unsaturated 5-6 member heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said aryl or heterocyclic substituent of R₈ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, hydroxy, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; wherein R₁₈ is selected from hydrogen and C₁₋₆alkyl;

R₉ is selected from hydrogen and C₁₋₆alkyl;

R₁₀ is selected from hydrogen and C₁₋₆alkyl;

R₁₁ is selected from hydrogen and C₁₋₆alkyl;

R₁₂ is selected from hydrogen and C₁₋₆alkyl; or R₁₁ and R₁₂ combine to form C(O); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds; with the proviso that the following compounds are excluded from the invention: 2-amino-1-(3-(benzo[d][1,3]dioxol-5-ylamino)-2-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone; 2-(2-methoxyphenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-phenyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(pyridin-3-yl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; and 2-(4-fluorophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine.

In a second aspect, the present invention provides a pharmaceutical composition which contains a compound selected from Formula Ia, Ib and Ic or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

In a third aspect, the present invention provides a method of treating a disease in an animal in which a compound of the invention can prevent, inhibit or ameliorate the pathology and/or symptomology of disease caused by a parasite (such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, Trypanosoma cruzi or a parasite of the Leishmania genus such as, for example, Leishmania donovani) which method comprises administering to the animal a therapeutically effective amount of a compound selected from Formula Ia, Ib and Ic or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compound selected from Formula Ia, Ib and Ic in the manufacture of a medicament for treating a disease caused by a parasite in an animal. The disease may be malaria, leishmaniasis and/or Chagas disease.

In a fifth aspect, the present invention provides a process for preparing compounds selected from Formula Ia, Ib and Ic and the N-oxide derivatives, prodrug derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alkyl” as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched. C₁₋₄-alkoxy includes, methoxy, ethoxy, and the like. Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl may be phenyl or naphthyl, preferably phenyl. “Arylene” means a divalent radical derived from an aryl group.

“Heteroaryl” is as defined for aryl where one or more of the ring members are a heteroatom selected from N, O, C(O) and S(O)₀₋₂. For example 5-10 member heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated. For example, C₃₋₁₀cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocyclic” means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—, wherein R is hydrogen, C₁-4alkyl or a nitrogen protecting group. For example, 3-8 member heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

“Halogen” (or halo) represents chloro, fluoro, bromo or iodo.

“Treat”, “treating” and “treatment” refer to a method of alleviating or abating a disease and/or its attendant symptoms. In the present description, the term “treatment” includes both prophylactic or preventative treatment as well as curative or disease suppressive treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as ill patients. This term further includes the treatment for the delay of progression of the disease.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with a parasite. In particular, the compounds can be used to treat malaria, leishmaniasis and/or Chagas disease.

In one embodiment, with reference to compounds of Formula Ia, Ib and Ic: R₁ is selected from —OR₁₃, —C(O)OR₁₃, —NR₁₃R₁₄, phenyl, pyridinyl, indolyl, azetidinyl, 1H-indazolyl, piperidinyl and pyrimidinyl; wherein R₁₃ is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, phenyl, benzyl, amino-butyl, hydroxy-ethyl, methoxy-ethyl, butoxy-ethyl, methoxy-propyl, —C(O)R₁₅, —C(O)OR₁₅, —X₁OR₁₅, —X₁C(NH)NHR₁₅, —X₁NHC(O)R₁₅ and X₁C(O)NHR₁₅; wherein X₁ is selected from a bond and C₁₋₄alkylene; and R₁₅ is selected from hydrogen, methyl, ethyl, propyl, butyl, t-butyl, trifluoromethyl and trifluoromethyl-carbonyl; R₁₄ is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, isobutyl, hydroxy-ethyl, difluoroethyl and isobutyl; wherein any phenyl, benzyl or heterocyclic of R₁ is optionally substituted with 1-3 radicals independently selected from halo, methyl, ethyl, trifluoromethoxy and trifluoromethyl; or R₁₃ and R₁₄ together with the nitrogen to which R₁₃ and R₁₄ are attached form pyrrolidinyl, morpholino, thiomorpholino and piperidinyl; wherein said heterocyclic form the combination of R₁₃ and R₁₄ is optionally substituted with 1 to 3 radicals independently selected from halo, trifluoromethyl, hydroxy and amino-ethyl.

In another embodiment, R₂ is selected from hydrogen, methyl, ethyl, isopropyl, propyl, isobutyl, butyl, t-butyl, trifluoromethyl, trifluoro-ethyl, phenyl, benzyl, phenethyl, cyclobutyl-methyl, cyclopentyl, cyclohexyl, cyclohexyl-methyl, hydroxy-methyl and 1-hydroxy-ethyl; wherein said phenyl, benzyl or phenethyl of R₂ is optionally substituted with 1 to 3 radicals independently selected from halo, methoxy, trifluoromethyl, hydroxy, amino, nitro, cyano, amino-methyl, methyl-sulfonyl-ethyl, methyl-carbonyl-amino, —NHR₁₇, —CH₂NHC(O)R₁₇ and —NHC(O)R₁₇; wherein R₁₇ is selected from hydrogen, ethyl, propyl, butyl and pentyl.

In another embodiment, R₃ is selected from hydrogen, methyl, methyl-carbonyl-amino-butyl, propyl-amino-carbonyl-methyl, carboxy-methyl, propyl-amino-carbonyl-methyl, butyl-amino-carbonyl-methyl, pentyl-amino-carbonyl-methyl, propyl-amino-carbonyl-ethyl, trifluoromethyl-carbonyl-amino-butyl, phenyl, benzyl-sulfanyl-methyl, benzoxy-carbonyl-methyl, methyl-sulfonyl-methyl, 1-(benzyloxy)ethyl, benzoxy-carbonyl-ethyl and benzoxy-carbonyl-amino.

In another embodiment, R₂ and R₃ together with the carbon atom to which R₂ and R₃ are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment, R₂ and R₁₃ together with the atoms to which R₂ and R₁₃ are attached form piperidinyl, cyclobutyl, pyrrolidinyl, morpholino, piperidinyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, 4-oxoazetidin-2-yl, indolyl, 2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl, oxopiperidin-3-yl or 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl.

In a further embodiment, R₄, R₅, R₉ and R₁₀ are independently selected from hydrogen and methyl; R₁₁ and R₁₂ are both hydrogen; or R₁₁ and R₁₂ combine to form C(O).

In a further embodiment, R₆ is selected from phenyl, cyclohexyl and pyridinyl; wherein said phenyl or pyridinyl of R₆ is optionally substituted by 1 to 3 radicals independently selected from halo, pentyl, hydroxy, methyl and methoxy.

In a further embodiment, R₇ is selected from hydrogen, methyl, ethyl and isopropyl; and R₈ is selected from phenyl, benzyl, benzo[d][1,3]dioxol-5-yl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl and pyrazolyl; wherein said phenyl, benzyl, benzo[d][1,3]dioxol-5-yl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl or pyrazolyl of R₈ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, trifluoromethoxy, dimethyl-amino, difluoromethoxy, carboxy, methoxy-carbonyl, methyl-sulfonyl-amino, methyl-sulfonyl, methyl-amino-carbonyl, phenyl, piperidinyl, piperidinyl-methyl, piperazinyl and piperazinyl-methyl.

In another embodiment is a compound of Formula Id:

in which: R₁ is —NH₂; R₂ and R₃ are independently selected from hydrogen and methyl; R₄ and R₅ are independently selected from hydrogen and methyl; R₆ is phenyl substituted with a fluoro; and R₈ is a phenyl substituted with 1 to 2 radicals independently selected from chloro and fluoro.

In a further embodiment are compounds selected from: 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone; 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one; and 2-amino-1-(3-(4-chlorophenylamino)-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone.

In a further embodiment are compounds selected from: 2-amino-1-{3-[(3,5-dimethylphenyl)amino]-2-phenyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(2H-1,3-benzodioxol-5-ylamino)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[3-(cyclopentylamino)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(cyclopentylamino)-2-phenyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-2-methyl-1-[2-phenyl-3-(phenylamino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; methyl 4-{[7-(2-amino-2-methylpropanoyl)-2-phenyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzoate; 2-amino-1-[2-(2-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(4-fluorophenyl)amino]-2-phenyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(4-fluorophenyl)amino]-2-(2,4,6-trifluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-[2-(3,5-difluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(4-fluorophenyl)amino]-2-(4-pentylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{2-cyclohexyl-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-(pyridin-3-ylamino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 4-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-phenylpropan-1-one; (2R)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-phenylpropan-1-one; 2-amino-1-{3-[(4-bromophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-(dimethylamino)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(benzylamino)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-(4-chlorophenyl)-3-(4-methylphenyl)imidazo[1,2-a]pyrazine; N-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}acetamide; N,2-bis(4-fluorophenyl)imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-[3-(cyclohexylamino)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; N,2-bis(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2,3-bis(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(methylamino)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(pyrrolidin-1-yl)ethan-1-one; 3-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(3-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(3-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(morpholin-4-yl)ethan-1-one; 4-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}-1$1̂{6},4-thiomorpholine-1,1-dione; 2-(3,3-difluoropiperidin-1-yl)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 7-[(1-aminocyclopropyl)carbonyl]-N,2-bis(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-{1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methyl-1-oxopropan-2-yl}acetamide; 2-amino-1-[2-(4-chlorophenyl)-3-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 7-benzyl-N,2-bis(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; benzyl N-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}carbamate; 2-amino-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 2-amino-1-[2-(4-fluoro-2-hydroxyphenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-fluorophenyl)amino]-2-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-fluorophenyl)amino]-2-(4-methoxyphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-bromophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-chlorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(3,3-difluoropyrrolidin-1-yl)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(3R)-3-fluoropyrrolidin-1-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(3S)-3-fluoropyrrolidin-1-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(4-fluoropiperidin-1-yl)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[4-(trifluoromethyl)piperidin-1-yl]ethan-1-one; 2-(4,4-difluoropiperidin-1-yl)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[3-(trifluoromethyl)piperidin-1-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(3-hydroxypiperidin-1-yl)ethan-1-one; 2-[(2,2-difluoroethyl)amino]-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3,5-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(3,5-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-(cyclopropylamino)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(2-methylpropyl)amino]ethan-1-one; 2-amino-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-{[4-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-{[4-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(3,3-difluoropiperidin-1-yl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(methylamino)ethan-1-one; 1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(3,3-difluoropiperidin-1-yl)ethan-1-one; 1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(methylamino)ethan-1-one; 2-amino-1-{3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(2,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(2,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxypropan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-phenylethan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H, 8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2R)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(3R)-piperidin-3-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(3S)-piperidin-3-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-[2-(diethylamino)ethyl]-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-{[(2S)-azetidin-2-yl]carbonyl}-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(2R)-pyrrolidin-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(2S)-pyrrolidin-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(2S)-piperidin-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(2R)-piperidin-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(3R)-pyrrolidin-3-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(3S)-pyrrolidin-3-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2R)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylethan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylethan-1-one; 1-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}cyclopropan-1-ol; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-3-methylbutan-1-one; N-[(5S)-5-amino-6-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-6-oxohexyl]acetamide; N-[(5S)-5-amino-6-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-6-oxohexyl]-2,2,2-trifluoroacetamide; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxypropan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; (1S,2S)-2-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}cyclopentan-1-ol; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-phenylpropan-1-one; 2-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxybutan-1-one; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-phenylpropan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3,3-dimethylbutan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-phenylpropan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2,2-diphenylethan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-(trifluoromethyl)butan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-methylpropan-1-one; 1-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}cyclopentan-1-ol; 1-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}cyclohexan-1-ol; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-4-phenylbutan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-2,2-dimethyl-3-(4-methylphenyl)propan-1-one; 4,4,4-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-3-methylbutan-1-one; (2S)-2-cyclohexyl-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-(4-methoxyphenyl)ethan-1-one; 2-(3,5-difluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methoxy-2-phenylethan-1-one; 2-(4-bromophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethan-1-one; 3,3,3-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methoxy-2-phenylpropan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-(3-hydroxyphenyl)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-(4-hydroxyphenyl)ethan-1-one; 2-(2-chlorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 2-(4-bromo-2-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; 2-(4-chlorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxyethan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-4-methylpentan-1-one; (3S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-3-phenylpropan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)imidazo[1,2-a]pyrazin-3-amine; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-phenylethan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-phenylethan-1-one; 7-[(1-aminocyclobutyl)carbonyl]-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-[(1-aminocyclopentyl)carbonyl]-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-[(1-aminocyclohexyl)carbonyl]-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-4,4,4-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-3-methylpentan-1-one; 2-amino-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-3-cyclohexyl-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxypropan-1-one; 2-(benzylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(dipropylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-2-(dipropylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(methylamino)-3-phenylpropan-1-one; benzyl (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-5-oxopentanoate; benzyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-4-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxobutanoate; tert-butyl N-[(5S)-5-{[(benzyloxy)carbonyl]amino}-6-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-6-oxohexyl]carbamate; 2-(cyclopropylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; N-[4-({2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}amino)butyl]acetamide; 2-(4-fluorophenyl)-7-{2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethyl}-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2,6-diamino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]hexan-1-one; (2S)-2-amino-3-(4-aminophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; N-[(5S)-5-amino-6-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-6-oxohexyl]butanamide; N-[(5S)-5-amino-6-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-6-oxohexyl]-1-(5-{2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl}pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide; N-{4-[(2S)-2-amino-3-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}acetamide; 2-[bis(2-hydroxyethyl)amino]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (4S)-4-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}azetidin-2-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxypropan-1-one; 2,2,2-trifluoro-N-[(2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-1-oxopropan-2-yl]acetamide; 6-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}-1,2,3,4-tetrahydropyrimidine-2,4-dione; {2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}urea; 1-{2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}guanidine; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(phenylamino)ethan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methylbutan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3,3-dimethylbutan-1-one; (3S)-3-amino-4-(4-bromophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; (3S)-3-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one; 2-(4-chlorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 2-(4-chlorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylpropan-1-one; 2-(4-fluorophenyl)-7-{[(6S)-1H,4H,5H,6H,7H-imidazo[4,5-c]pyridin-6-yl]carbonyl}-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-(dimethylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-phenylpropan-1-one; 2-[4-(2-aminoethyl)piperidin-1-yl]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(4-fluorophenyl)-7-[(4-methanesulfonylphenyl)methyl]-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[4-(morpholin-4-yl)phenyl]methyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[4-(4-methylpiperazin-1-yl)phenyl]methyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-{[4-(diethylamino)phenyl]methyl}-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-({4-[3-(dimethylamino)propoxy]phenyl}methyl)-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[4-(pyridin-4-yl)phenyl]methyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; tert-butyl N-[(2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxo-3-(4-propanamidophenyl)propan-2-yl]carbamate; tert-butyl N-[(2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1 l-oxo-3-(propylcarbamoyl)propan-2-yl]carbamate; N-{4-[(2S)-2-amino-3-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}propanamide; (4S)-4-amino-5-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-5-oxo-N-propylpentanamide; (3S)-3-amino-4-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-N-propylbutanamide; 3-amino-4,4,4-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; 2-(3-fluorophenyl)-N-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 7-{[(1S,2R)-2-aminocyclopentyl]carbonyl}-2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3,3,3-trifluoropropan-1-one; (2R)-2-amino-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; N-{4-[(2S)-2-amino-3-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}butanamide; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methoxypropan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(2R)-oxolan-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[(2S)-oxolan-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenoxybutan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenoxypropan-1-one; 2-(3-chlorophenoxy)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(pyrimidin-4-yl)ethan-1-one; N-(4-chloro-3-fluorophenyl)-2-(3-fluorophenyl)imidazo[1,2-a]pyrazin-3-amine; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methyl-2-(2-methylphenoxy)butan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-[(oxan-4-yl)carbonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-ethoxy-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(4-hydroxyphenyl)propan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(oxolan-2-yl)ethan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-[(oxolan-3-yl)carbonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-3-[4-(aminomethyl)phenyl]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 2-(1-ethylpiperidin-4-yl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(oxolan-3-yl)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(oxan-2-yl)ethan-1-one; N-(4-chloro-3-fluorophenyl)-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-({4-[(2S)-2-amino-3-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}methyl)butanamide; N-({4-[(2S)-2-amino-3-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}methyl)propanamide; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(piperidin-4-yl)ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3,3,3-trifluoropropan-1-one; (2R)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-phenylpropan-1-one; (2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-phenylpropan-1-one; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylbutan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylbutan-1-one; 2-cyclopentyl-1-[2-(4fluorophenyl)-3-[(4-fluorophenyl)-3-(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(pyridin-4-yl)ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-(3,5-dichlorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methyl-2-phenylbutan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(4-methylphenyl)ethan-1-one; 2-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-hydroxy-3-methylbutan-1-one; 1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-3-methylbutan-1-one; benzyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-4-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-oxobutanoate; benzyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-4-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxobutanoate; tert-butyl N-[(2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-nitrophenyl)-1-oxopropan-2-yl]carbamate; tert-butyl N-[(2S)-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(4-nitrophenyl)-1-oxopropan-2-yl]carbamate; (3S)-3-{[(tert-butoxy)carbonyl]amino}-4-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-oxobutanoic acid; (3S)-3-{[(tert-butoxy)carbonyl]amino}-4-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxobutanoic acid; tert-butyl N-[(2S)-3-(4-aminophenyl)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-1-oxopropan-2-yl]carbamate; tert-butyl N-[(2S)-3-(4-aminophenyl)-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxopropan-2-yl]carbamate; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-2,2-dimethylpropan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one; tert-butyl N-[(2S)-3-(3-aminophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxopropan-2-yl]carbamate; tert-butyl N-[(2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-1-oxo-3-(propylcarbamoyl)propan-2-yl]carbamate; tert-butyl N-[(2S)-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxo-3-(propylcarbamoyl)propan-2-yl]carbamate; 4-{[2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; tert-butyl N-[(2S)-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxo-3-(pentylcarbamoyl)propan-2-yl]carbamate; 1-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}-N,N-dimethylpyrrolidin-3-amine; tert-butyl N-[(2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-1-oxo-3-(4-pentanamidophenyl)propan-2-yl]carbamate; tert-butyl N-[(2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-1-oxo-3-(4-propanamidophenyl)propan-2-yl]carbamate; tert-butyl N-[(2S)-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxo-3-(4-pentanamidophenyl)propan-2-yl]carbamate; (3S)-3-amino-4-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-oxo-N-propylbutanamide; (3S)-3-amino-4-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-N-propylbutanamide; (3S)-3-amino-4-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-N-pentylbutanamide; N-{4-[(2S)-2-amino-3-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-oxopropyl]phenyl}pentanamide; N-{4-[(2S)-2-amino-3-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-oxopropyl]phenyl}propanamide; N-{4-[(2S)-2-amino-3-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}pentanamide; N-{4-[(2S)-2-amino-3-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-oxopropyl]phenyl}propanamide; N-(4-chlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 4-{[7-(2-amino-2-methylpropanoyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 4-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 4-{[2-(4-fluorophenyl)-7-(3-hydroxy-3-methylbutanoyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 2-(3-methylphenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; tert-butyl N-[(2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-1-oxo-3-[4-(pentylamino)phenyl]propan-2-yl]carbamate; 2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxo-1-phenylethyl propanoate; 2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxo-1-phenylethyl butanoate; 2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxo-1-phenylethyl pentanoate; 2-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-1-(4-fluorophenyl)ethan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-[4-(pentylamino)phenyl]propan-1-one; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[4-(3-methylpiperidin-1-yl)piperidin-1-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-7-{[4-(piperidin-1-yl)piperidin-1-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-7-{[4-(4-fluorophenyl)piperidin-1-yl]carbonyl}-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; ethyl 1-{[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}piperidine-3-carboxylate; N-[2-(diethylamino)ethyl]-2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carboxamide; 2-(3,4-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(3-chlorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(2,4-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-[(2-hydroxypropyl)amino]-3-phenylpropan-1-one; (2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-[(2-methoxyethyl)amino]-3-phenylpropan-1-one; 3-{[(5R,8S)-2,8-dibenzyl-3-methyl-5-(2-phenylethyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]carbonyl}pyridine; (2R)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxypropan-1-one; (2R,3S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxybutan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-methanesulfonylbutan-1-one; (3R)-3-amino-4-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-oxobutanoic acid; (2R)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methanesulfonylpropan-1-one; (5R,8R)-2,8-dibenzyl-3-methyl-5-(2-phenylethyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N-[(1S)-2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxo-1-phenylethyl]propanamide; N-[(1S)-2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxo-1-phenylethyl]butanamide; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)(methyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)(methyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; (2S)-2-(butylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-phenylethan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(pentylamino)-2-phenylethan-1-one; N-tert-butyl-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-[(1S)-2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxo-1-phenylethyl]-1-(5-{2-oxo-hexahydro-H-thieno[3,4-d]imidazolidin-4-yl}pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide; 3-amino-2-(4-fluorophenyl)-7-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methoxypropan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(pyridin-4-yl)ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(1H-indol-1-yl)ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(1-ethylpiperidin-4-yl)ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(phenylamino)ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(H-indazol-3-yl)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(propylamino)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(pentylamino)ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(2-methoxyethyl)amino]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(3-methoxypropyl)amino]ethan-1-one; (2R)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-phenylpropan-1-one; (2S,3S)-2-amino-3-(benzyloxy)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}butan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(1,3-thiazol-4-yl)propan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-fluorophenyl)propan-1-one; (2S,3S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylpentan-1-one; (2R)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(3,4-difluorophenyl)propan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methyl-2-(methylamino)propan-1-one; 7-{[(2S)-azetidin-2-yl]carbonyl}-N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-methylpentan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-[(morpholin-3-yl)carbonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-phenylpropan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-cyclobutylpropan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3,3-dimethylbutan-1-one; (2R)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; 4-[(2S)-2-amino-3-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-oxopropyl]benzonitrile; 2-(4-fluorophenyl)-6-methyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(2,5-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-phenyl-2-(phenylamino)ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1-one; (2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-phenylpropan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-[4-fluoro-3-(trifluoromethyl)phenyl]ethan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-phenoxyethan-1-one; 5-({3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}carbonyl)piperidin-2-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-{[(2S)-pyrrolidin-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 3-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4,4,4-trifluorobutan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-{[(3S)-pyrrolidin-3-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-methylphenyl)propan-1-one; N-(4-chloro-3-fluorophenyl)-7-[(2,3-dihydro-1H-isoindol-1-yl)carbonyl]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-7-{[(2S)-2,3-dihydro-1H-indol-2-yl]carbonyl}-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (3S)-3-amino-4-(4-bromophenyl)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}butan-1-one; (2R)-2-amino-3-(4-bromophenyl)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-{[(4-methoxyphenyl)methyl]sulfanyl}propan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-{[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4,4,4-trifluorobutan-1-one; 2-(2-butoxyethoxy)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-ethoxy-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(2-methoxyethoxy)ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-6-methyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 5-{[7-(2-amino-2-methylpropanoyl)-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-fluorobenzonitrile; N-(4-methylphenyl)-2-(pyridin-4-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-{[2-chloro-4-(trifluoromethyl)phenyl]amino}-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methylbutan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-{[(2R)-oxolan-2-yl]carbonyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(1-methyl-1H-indol-3-yl)ethan-1-one; (2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-4-methylpentan-1-one; 1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(2-fluorophenyl)propan-1-one; (2R)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-methylbutan-1-one; 2-[(3-chlorophenyl)amino]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(4-methylphenyl)amino]ethan-1-one; 2-(4-chloro-3-fluorophenyl)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(4-methoxyphenyl)amino]-2-methylpropan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(3,4-dichlorophenyl)ethan-1-one; 2-amino-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-[(morpholin-2-yl)carbonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-[4-(trifluoromethyl)phenyl]ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(4-chlorophenyl)ethan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-[(quinolin-6-yl)carbonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(4-methylphenyl)amino]-2-phenylethan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-7-[(4-methylmorpholin-2-yl)carbonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(2-fluorophenyl)amino]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methyl-2-(phenylamino)propan-1-one; 2-amino-1-(3-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl)-2-methylpropan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methyl-2-(methylamino)butan-1-one; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-methyl-2-(methylamino)pentan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-methyl-2-(methylamino)pentan-1-one; 2-amino-1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-[(2,6-dimethylphenyl)amino]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 2-amino-1-[2-(2-methoxyphenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-methylphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(3-chlorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-[(2,4-dimethylphenyl)amino]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methyl-2-[(4-methylphenyl)amino]propan-1-one; 2-amino-1-[2-(2,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-2-[benzyl(methyl)amino]-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(methylamino)hexan-1-one; 1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(4-methylphenyl)ethan-1-one; (2R)-1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(methylamino)pentan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}butan-1-one; (2R)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-methylpentan-1-one; 2-amino-1-[2-(2,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; (2S)-2-amino-1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methylbutan-1-one; 2-amino-1-[2-(3-chlorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-2-methyl-1-{3-[(4-methylphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; 2-(tert-butylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-3-(4-chlorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-(methylamino)propan-1-one; (2S)-2-amino-3-cyclopropyl-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2R)-2-(benzylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-(benzylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-2-cyclopropyl-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-2-amino-3-(3,4-difluorophenyl)-1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(3,4-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-[(4-methylphenyl)amino]propan-1-one; 2-amino-1-[2-(2,5-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3,4-dichlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; N-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; N-(4-chloro-3-fluorophenyl)-N-ethyl-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2R)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methyl-2-(methylamino)butan-1-one; 2-(4-fluorophenyl)-8,8-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(2,5-difluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 4-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 4-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 2-amino-1-{3-[(3,4-difluoro-5-methoxyphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(4-fluoro-3,5-dimethylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; (2S)-2-amino-3-cyclobutyl-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2R)-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(1,3-thiazol-4-yl)propan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-methylphenyl)propan-1-one; (2S)-2-amino-3-(3,4-difluorophenyl)-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(4-fluorophenyl)ethan-1-one; (2S)-2-amino-2-cyclopropyl-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; (2S)-2-amino-3-cyclopropyl-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-methylpentan-1-one; (2S)-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-methylbutan-1-one; 7-{[(2S)-azetidin-2-yl]carbonyl}-N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S,3S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylpentan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-fluorophenyl)propan-1-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-fluorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-ethyl-N-(3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}propan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-cyclopropylethan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-cyclopropylpropan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-cyclobutylpropan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4-methylpentan-1-one; (2S,3S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-methylpentan-1-one; (2S)-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-methylbutan-1-one; (2R)-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(4-fluorophenyl)ethan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-fluorophenyl)propan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(4-methylphenyl)propan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(3,4-difluorophenyl)propan-1-one; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-(1,3-thiazol-4-yl)propan-1-one; 7-{[(2S)-azetidin-2-yl]carbonyl}-N-(4-chlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3,3-dimethylbutan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methylbutan-1-one; (2S)-2-amino-2-cyclopropyl-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-2-amino-3-cyclopropyl-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-3-cyclobutyl-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H, 8H-imidazo[1,2-a]pyrazin-7-yl]-4-methylpentan-1-one; (2S,3S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methylpentan-1-one; (2S)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; (2R)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; (2S)-2-amino-2-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-2-amino-3-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(4-methylphenyl)propan-1-one; (2S)-2-amino-3-(3,4-difluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(1,3-thiazol-4-yl)propan-1-one; 7-{[(2S)-azetidin-2-yl]carbonyl}-N,2-bis(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3,3-dimethylbutan-1-one; (2S)-2-amino-3-cyclobutyl-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-4-methylpentan-1-one; (2S,3S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-methylpentan-1-one; (2S)-2-amino-2-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(4-methylphenyl)propan-1-one; (2S)-2-amino-3-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-3-(3,4-difluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(1,3-thiazol-4-yl)propan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-cyclopropylethan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3-cyclopropylpropan-1-one; (2S)-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-hydroxy-3-methylbutan-1-one; (2S)-2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-(4-fluorophenyl)ethan-1-one; (2S)-2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-3,3-dimethylbutan-1-one; 2-amino-1-{3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; N,2-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluoro-3-methylphenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-(3-chloro-4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-chloro-3-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(3-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-{[3-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(3-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (2S)-2-amino-3-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2,4-dimethylpentan-1-one; (2S)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-2-methylpropan-1-one; (2R)-2-amino-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-2-methylpropan-1-one; 3-[(3,4-dichlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 4-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N-(3-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-8,8-dimethyl-N-[3-(trifluoromethyl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2,2,2-trifluoro-1-[2-(4-fluorophenyl)-3-[(3-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluoro-3-methylphenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluoro-3-methylphenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(3-chloro-4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-chloro-3-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-chloro-3-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 5-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-fluorobenzonitrile; 2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzoic acid; 2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 5-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzoic acid; 5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 2,2,2-trifluoro-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-{[3-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; tert-butyl N-{1-[3-bromo-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methyl-1-oxopropan-2-yl}carbamate; 2-amino-1-[3-(cyclohexylamino)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3-chloro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3-fluoro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 4-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-chlorobenzonitrile; 5-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; N,2-bis(4-fluorophenyl)-5,5,7,8,8-pentamethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 2-(4-fluorophenyl)-5,5,7,8,8-pentamethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-5,5,7,8,8-pentamethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; tert-butyl N-{2-[2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}carbamate; N-(3-fluoro-4-methylphenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-chloro-4-methylphenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-8,8-dimethyl-3-[(3,4,5-trifluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(6-methoxypyridin-3-yl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylpyridin-2-yl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-chloro-4-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; (8R)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(3,4-difluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N-(3-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}phenyl)methanesulfonamide; 3-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-N-methylbenzamide; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(3,4,5-trifluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(4-fluorophenyl)-8,8-dimethyl-N-(3,4,5-trifluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (8 S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8S)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8R)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-(quinolin-3-ylamino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(4-methanesulfonylphenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-methanesulfonylphenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-(4-fluorophenyl)-8,8-dimethyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-[2-(4-fluorophenyl)-6,6-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 5-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-fluorobenzonitrile; 2-(4-fluorophenyl)-6,6-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N,2-bis(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-fluoro-5-{[2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 2-(3-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(3,4-dichlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 5-{[7-(2-amino-2-methylpropanoyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 4-{[7-(2-amino-2-methylpropanoyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-chlorobenzonitrile; (2S)-1-[2-(3-fluorophenyl)-5,5-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-methylbutan-1-one; 2-amino-1-[2-(3-fluorophenyl)-5,5-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(3-fluorophenyl)-5,5-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[(8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[(8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[(8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 3-[(3-fluoro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (2S)-1-[2-(3-fluorophenyl)-5,5-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-phenylpropan-1-one; 2-amino-1-{3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(1-ethyl-1H-pyrazol-5-yl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[(8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 3-[(3-fluoro-4-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N,2-bis(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-methylphenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 5-{[2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(3-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(3-fluorophenyl)-3-[(4-fluorophenyl)amino]-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3,4-difluorophenyl)amino]-2-(3-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3-chloro-4-fluorophenyl)amino]-2-(3-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-fluoro-3-methylphenyl)amino]-2-(3-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chloro-3-methylphenyl)amino]-2-(3-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-amino-1-{3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 5-{[7-(2-amino-2-methylpropanoyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 2-amino-1-{3-[(3-fluoro-4-methylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-{3-[(3-chloro-4-methylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-(3-{[3-chloro-4-(trifluoromethyl)phenyl]amino}-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl)-2-methylpropan-1-one; 2-amino-1-(3-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl)-2-methylpropan-1-one; 4-{[7-(2-amino-2-methylpropanoyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-(trifluoromethyl)benzonitrile; 5-{[7-(2-amino-2-methylpropanoyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-fluorobenzonitrile; 2-amino-1-{3-[(3,4-dimethylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(3-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(3-chlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-{[3-(trifluoromethoxy)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(4-ethylphenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 2-amino-1-(3-{[4-(difluoromethoxy)phenyl]amino}-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl)-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-{[4-(trifluoromethoxy)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-{3-[(3,5-dichlorophenyl)amino]-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2-methylpropan-1-one; 10-[(3,4-difluorophenyl)amino]-11-(4-fluorophenyl)-4,4-dimethyl-3,6,9,12-tetraazatricyclo[7.3.0.0{2,6}]dodeca-1(12),2,10-trien-5-one; 10-[(3,4-difluorophenyl)amino]-11-(4-fluorophenyl)-4,4-dimethyl-3,6,9,12-tetraazatricyclo[7.3.0.0{2,6}]dodeca-1(12),10-dien-5-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-phenylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-ethylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-{[4-(trifluoromethoxy)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-{[3-(trifluoromethoxy)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3-chlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-{[3-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 3-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 2-amino-1-{3-[(3,4-dimethylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 4-{[7-(2-aminoacetyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-(trifluoromethyl)benzonitrile; 2-amino-1-{3-[(3,5-dimethylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-(3-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl)ethan-1-one; 2-amino-1-(3-{[3-chloro-4-(trifluoromethyl)phenyl]amino}-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl)ethan-1-one; 2-amino-1-{3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4,4-difluorocyclohexyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-phenylcyclohexyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-{[4-(trifluoromethyl)cyclohexyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-tert-butylcyclohexyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(2-methylcyclohexyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(cycloheptylamino)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(3,3,5-trimethylcyclohexyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[3-(dimethylamino)pyrrolidin-1-yl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[4-(piperidin-1-yl)piperidin-1-yl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(cyclopentylamino)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(cyclobutylamino)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-(oxan-4-ylamino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(2-methylbutyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-5,5-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chlorophenyl)(methyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 7-[2-(dimethylamino)ethyl]-2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 7-[2-(dimethylamino)ethyl]-3-[(3-fluoro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-methylphenyl)amino]-7-[2-(dimethylamino)ethyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 7-[2-(dimethylamino)ethyl]-3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-methylphenyl)amino]-7-[2-(dimethylamino)ethyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-7-[2-(dimethylamino)ethyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 7-(azetidin-3-ylmethyl)-3-[(4-fluoro-3-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 7-(2-aminoethyl)-2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-7-(2-hydroxyethyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 7-(3-aminopropyl)-3-[(4-fluoro-3-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-fluoro-3-methylphenyl)amino]-2-(3-fluorophenyl)-7-(3-hydroxypropyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-fluoro-3-methylphenyl)amino]-2-(3-fluorophenyl)-7-(3-methoxypropyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 4-{3-[(4-fluoro-3-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}butanoic acid; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)methyl]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)methyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3,4-difluorophenyl)methyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)methyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylpiperazin-1-yl)methyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(cyclohexylmethyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-3-(4-methylphenyl)propan-1-one; 2-amino-4-(3-fluorophenyl)-1-[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; 2-amino-4-(4-chlorophenyl)-1-[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]butan-1-one; 2-amino-3-cyclohexyl-1-[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]propan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2,3-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; N,2-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-3-carboxamide; 7-(2-aminoacetyl)-N,2-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-3-carboxamide; 2-amino-1-[3-(4-fluorophenoxy)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(4-chlorophenoxy)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(3,4-difluorophenoxy)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[3-(4-fluoro-3-methylphenoxy)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)sulfanyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(3-fluorophenyl)sulfanyl]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)sulfanyl]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(4-chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3,5-dimethylphenyl)sulfanyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3,4-difluorophenyl)sulfanyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3-fluorobenzene)sulfinyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-fluorobenzene)sulfinyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylbenzene)sulfinyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; 2-amino-1-{3-[(3,5-dimethylbenzene)sulfinyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(3,4-difluorobenzene)sulfinyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; 2-amino-1-{3-[(4-chlorobenzene)sulfinyl]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}ethan-1-one; and 2-amino-1-[2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylbenzene)sulfonyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one.

In an embodiment of the invention are compounds selected from: N-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}-3-phenylpropanamide; N-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}-3-{8-oxatricyclo[7.4.0.0{2,7}]trideca-1(9),2,4,6,10,12-hexaen-4-yl}propanamide; N-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}-3-(3-phenylpropanamido)propanamide; N-{2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}-3-(3-{8-oxatricyclo[7.4.0.0 {2,7}]trideca-1(9),2,4,6,10,12-hexaen-4-yl}propanamido)propanamide; N-[3-({2-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}amino)propyl]-3-phenylpropanamide; 5,5-difluoro-3-(3-(2-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethylamino)-3-oxopropyl)-7-phenyl-5H-dipyrrolo[1,2-c:1′,2′-f][1,3,2]diazaborinin-4-ium-5-uide; and 5,5-difluoro-2-(3-(6-(2-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethylamino)-6-oxohexylamino)-3-oxopropyl)-7-(4-methoxyphenyl)-1,3-dimethyl-5H-dipyrrolo[1,2-c:1′,2′-f][1,3,2]diazaborinin-4-ium-5-uide.

In an embodiment of the invention are compounds selected from: N-(4-methylphenyl)-2-(pyridin-3-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyridin-3-amine; 2-cyclohexyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(diphenylmethyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(2-nitrophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-[2-(thiophen-2-yl)phenyl]-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-[2-(difluoromethoxy)phenyl]-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(2-bromophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-{2-[2-(diethylamino)ethoxy]phenyl}-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-[2-(trifluoromethyl)phenyl]-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(2-{3-[(2,4,4-trimethylpentan-2-yl)amino]imidazo[1,2-a]pyridin-2-yl}phenoxy)ethan-1-ol; 2-[2-(furan-2-yl)phenyl]-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(4-fluorophenyl)-6-methyl-N-(4-methylphenyl)imidazo[1,2-a]pyridin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyridin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyridin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)imidazo[1,2-a]pyridin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-amine; 2-(4-fluorophenyl)-6-methyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyridin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-6-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyridin-3-amine; 8-(3,4-difluorophenylamino)-9-(4-fluorophenyl)-2,2-dimethyl-5,6-dihydrodiimidazo[1,2-a:2′,1′-c]pyrazin-3(2H)-one; and 8-(3,4-difluorophenylamino)-9-(4-fluorophenyl)-2,2-dimethyl-1,2,5,6-tetrahydrodiimidazo[1,2-a:2′,1′-c]pyrazin-3(10bH)-one.

In a further embodiment of the invention is a method for treating a Plasmodium related disease in a subject to prevent, inhibit or ameliorate the pathology and/or symptamology of the Plasmodium related disease, comprising administering to a subject, in vivo or in vitro, a therapeutically effective amount of a compound of the invention alone or in combination with a second agent.

In a further embodiment is a method for treating a Plasmodium related disease in a subject to prevent, inhibit or ameliorate the pathology and/or symptamology of the Plasmodium related disease, comprising administering to a subject, in vivo or in vitro, a therapeutically effective amount of a compound alone or in combination with a second agent, wherein the compound is selected from: 2-amino-1-(3-(benzo[d][1,3]dioxol-5-ylamino)-2-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone; 2-(2-methoxyphenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-phenyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; 2-(pyridin-3-yl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine; and 2-(4-fluorophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine.

In a further embodiment, the Plasmodium related disease is malaria.

In a further embodiment, the second agent is selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent. The anti-malarial drug is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, and pyronaridine.

In a further embodiment, the compounds of the invention can be administered prior to, simultaneously with, or after the second agent.

In a further embodiment, the subject is a human.

Pharmacology and Utility

Compounds of the invention are useful in the treatment and/or prevention of infections such as those caused by Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria, trypanosoma cruzi and parasites of the Leishmania genus, such as, for example, Leishmania donovani.

Malaria is an infectious disease caused by four protozoan parasites: Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world and over the last few decades the malaria burden has steadily increased. An estimated 1-3 million people die every year from malaria—mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives.

Leishmaniasis is caused by one or more than 20 varieties of parasitic protozoa that belong to the genus Leishmania, and is transmitted by the bite of female sand flies. Leishmaniasis is endemic in about 88 countries, including many tropical and sub-tropical areas.

There are four main forms of Leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form and is caused by the parasite Leishmania donovani. Patients who develop visceral leishmaniasis can die within months unless they receive treatment. The two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®). Sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem. In addition, the treatment is relatively long and painful, and can cause undesirable side effects.

Human African Trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. The parasites concerned are protozoa belonging to the Trypanosoma Genus. They are transmitted to humans by tsetse fly (Glossina Genus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites.

Chagas disease (also called American Trypanosomiasis) is another human parsitic disease that is endemic amongst poor populations on the American continent. The disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking insects. The human disease occurs in two stages: the acute stage, which occurs shortly after infection and the chronic stage, which can develop over many years. Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle and sometimes dilation of the digestive tract, as well as weight loss. Untreated, the chronic disease is often fatal.

The drugs currently available for treating Chagas disease are Nifurtimox and benznidazole. However, problems with these current therapies include their diverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Furthermore, treatment is really only effective when given during the acute stage of the disease. Resistance to the two frontline drugs has already occurred. The antifungal agent Amphotericin b has been proposed as a second-line drug, but this drug is costly and relatively toxic.

The phylum, Apicomplexa, contains many members that are human or animal pathogens including, but not limited to, Plasmodium spp. (Malaria), Toxoplasma gondii (congenital neurological defects in humans), Eimeria spp. (poultry and cattle pathogens), Cryptosporidia (opportunistic human and animal pathogens), Babesia (cattle parasites) and Theileria (cattle parasites). The pathogenesis associated with these parasitic diseases is due to repeated cycles of host-cell invasion, intracellular replication and host-cell lysis. Therefore, understanding parasite proliferation is essential for development of novel drugs and vaccines, for example, to treat malaria.

In vertebrate hosts, the parasite undergoes two main phases of development, the hepathocytic and erythrocytic phases, but it is the erythrocytic phase of its life cycle that causes severe pathology. During the erythrocytic phase, the parasite goes through a complex but well synchronized series of stages, suggesting the existence of tightly regulated signaling pathways.

Calcium serves as an intracellular messenger to control synchronization and development in the erythrocytic life phase. The Plasmodium spp. genomes reveal many sequence identities with calcium binding/sensing protein motifs that include Pf39, calmodulin, and calcium dependent protein kinases (CDPKs). Plasmodium CDPKs, Plasmodium CDPK3 and 4, have been shown to be involved in mosquito infection. CDPK4 has been demonstrated to be essential for the sexual reproduction in the midgut of mosquito by translating the calcium signal into a cellular response and regulating cell cycle progression in the male gametocyte. CDPK3 regulates ookinete gliding motility and penetration of the layer covering the midgut epithelium. P. falciparum CDPK1 (PfCDPK1) is expressed during late schizogony of blood stage and in the infectious sporozoite stage and is secreted to the parasitophorous vacuole by an acylation-dependent mechanism. It can be myristoylated and is abundantly found in detergent-resistant membrane fractions isolated from schizogony-phase parasites. Ontology based pattern identification analysis reveals that PfCDPK1 is clustered with genes associated with either parasite egress or erythrocyte invasion. Direct inhibition of PfCDPK1 can arrest the parasite erythrocytic life cycle progression in the late schizogony phase.

Therefore, kinase activity is distributed in all the stages of P. falciparum parasite maturation and kinase inhibitors of the present invention can be used for treating Plasmodium related diseases. In particular, kinase inhibitors of the present invention can be a route for treating malaria by inhibiting the kinase PfCDPK1. The in vitro cellular assay, infra, can be used to assess the activity of compounds of the invention against a variety of malarial parasite strains.

Compounds of the invention are inactive against mitogen-activated protein kinase-activated protein kinase 2 (MapKap2 or MK-2). For example, 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone (example 412) and 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one (Example 29) exhibit only 7% and 15% inhibition, respectively, in a single point concentration on this enzyme.

Compounds of the invention are relatively inactive against cannabinoid receptor 1 (CB1). For example, 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone (example 412) and 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one (Example 29) have an IC₅₀ of 24 μM and greater than 30 μM, respectively.

In accordance with the foregoing, the present invention further provides a method for preventing or treating malaria in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of a compound selected from Formula Ia, Ib, Ic or a pharmaceutically acceptable salt thereof. The required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.

Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). Non-limiting examples of compounds which can be used in combination with compounds of the invention are known anti-malarial drugs, for example, proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, etc.

Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the Reaction Schemes 1-5; R₂, R₃, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁ and R₁₂ are as defined in the Summary of the Invention. The following reaction schemes are given to be illustrative, not limiting, descriptions of the synthesis of compounds of the invention:

Reagents and Conditions:

(a) HClO₄, MeOH, rt; (b) Pd/C (or PtO₂), H₂, MeOH, rt; (c) HATU, DIEA, DMF, rt; (d) TFA, DCM, rt

Reagents and Conditions:

(a) HClO₄, MeOH, rt; (b) TFA, DCM, rt; (c) Pd₂(dba)₃, XantPhos, Cs₂CO₃, Dioxane, 140° C.

Reagents and Conditions:

(a) Cs₂CO₃, DMF, rt; (b) NH₄OAc, Dean-Stark, Toluene, reflux; (c) ethyl 2-bromoacetate, Cs₂CO₃, DMF, rt; (d) Pd/C, H₂, MeOH, rt; (e) LAH or BH₃.Me₂S, THF, reflux; (f) N-Boc-glycine, HATU, DIEA, DMF, rt; (g) Br₂, DCM/AcOH, rt; (h) p-toluidine, Pd₂(dba)₃, Xantphos, Cs₂CO₃, Dioxane, 140° C.; (i) TFA, DCM, rt.

Reagents and Conditions:

(a) Cs₂CO₃, DMF, rt; (b) NH₄OAc, Dean-Stark, Toluene, reflux; (c) 3-bromo-2-methylprop-1-ene, Cs₂CO₃, DMF, rt; (d) microwave, AcOH/MsOH, 210° C.; (e) N-Boc-glycine, HATU, DIEA, DMF, rt; (f) Br₂, DCM/AcOH, rt; (g) 4-chloroaniline, Pd₂(dba)₃, Xantphos, Cs₂CO₃, Dioxane, 140° C.; (h) 6N HCl, Dioxane, reflux.

Reagents and Conditions:

(a) Cs₂CO₃, DMF, rt; (b) NH₄OAc, Dean-Stark, Toluene, reflux; (c) ethyl 2-bromoacetate, Cs₂CO₃, DMF, rt; (d) Pd/C, H₂, MeOH, rt; (e) PMBCl, KOH, THF, rt; (f) MeI, NaH, DMF, rt; (g) BH₃.Me₂S, THF, reflux; (h) Br₂, DCM/AcOH, rt; (i) p-toluidine, Pd₂(dba)₃, Xantphos, Cs₂CO₃, Dioxane, 150° C.; (j) TFA, 70° C.; (k) N-Boc-glycine, HATU, DIEA, DMF, rt; (1) TFA, DCM, rt.

Detailed descriptions of the synthesis of compounds of the Invention are given in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention, for example, fumarate salts, can be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, “Protecting Groups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, which involves:

(a) that of reaction scheme 1, 2, 3, 4 and/or 5; and

(b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention to a non-salt form;

(d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;

(f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used.

EXAMPLES

The present invention is further exemplified, but not limited, by the following Examples (Table 2) and intermediates (Reference compounds—Table 1) that illustrate the preparation of compounds of the invention.

TABLE 1 Physical Data MS (m/z) and/or Compound Structure ¹H NMR Ref. comp. 1

[M + H] = 335.2 ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (d, J = 7.2 Hz, 2H), 7.91-7.94 (m, 3H), 7.21-7.27 (m, 3H), 6.59 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 5.99 (dd, J = 2.0, 9.2 Hz, 1H), □□5.83 (s, 2H), 4.48 (s, 2H), 3.89 (s, 2H), 3.38 (s, 2H). Ref. comp. 2

[M + H] = 319.2 ¹H NMR (CDCl₃, 400 MHz) δ 7.34 (s, 2H), 7.10 (s, 2H), 6.79-6.81 (m, 2H), 6.70-6.74 (m, 1H), 6.40 (br., 1H), 5.19 (s, 2H), □□4.22 (s, 2H), 3.92 (s, 2H), 1.98 (s, 6H). Ref. comp. 3

[M + H] = 301.2 Ref. comp. 4

[M + H] = 283.2 Ref. comp. 5

[M + H] = 291.2 Ref. comp. 6

[M + H] = 349.2 Ref. comp. 7

[M + H] = 327.2 Ref. comp. 8

[M + H] = 309.2 Ref. comp. 9

[M + H] = 363.1 Ref. comp. 10

[M + H] = 345.1 Ref. comp. 11

[M + H] = 379.2 Ref. comp. 12

[M + H] = 315.2 Ref. comp. 13

[M + H] = 310.2 Ref. comp. 14

[M + H] = 315.0 Ref. comp. 15

[M + H] = 387.1 Ref. comp. 16

[M + H] = 323.2 Ref. comp. 17

[M + H] = 327 ¹H NMR: (300 MHz, DMSO-d₆): δ 7.81-7.72 (m, 2H), 7.11 (m, 2H), 6.97 (m, 2H,), 6.56-6.52 (m, 2H), 3.86 (s, 2H), 3.55 (m, 2H), 3.02 (m, 2H) Ref. comp. 18

[M + H] = 311.9 Ref. comp. 19

[M + H] = 229 ¹H NMR (300 MHz, CDCl₃): δ 8.82 (s, 1H), 8.28 (d, J = 4.8 Hz, 1H) 8.05- 8.09 (m, 2H) 7.76 (d, J = 4.5 Hz, 1H) 7.27- 7.33 (m, 2H) 5.79 (s, 2H) Ref. comp. 20

[M + H] = 327.2 Ref. comp. 21

[M + H] = 324.3 Ref. comp. 22

[M + H] = 343.2 Ref. comp. 23

[M + H] = 323.2 Ref. comp. 24

[M + H] = 339.1 Ref. comp. 25

[M + H] = 387.1 Ref. comp. 26

[M + H] = 343.2 Ref. comp. 27

[M + H] = 345.1 Ref. comp. 28

[M + H] = 377.1 Ref. comp. 29

[M + H] = 323 ¹H NMR (400 MHz, CD₃OD) δ 7.73(d, J = 6.8 Hz, 2H), 7.00-6.99 (m, 4H), 6.49 (d, J = 8.0 Hz, 2H), 4.01 (s, 2H), 3.72(s, 2H), 3.72(s, 2H), 3.15(s, 2H), 2.19(s, 3H). Ref. comp. 30

[M + H] = 343 ¹H NMR-: (300 MHz, DMSO-d₆): δ□ 7.94(s, 1H), 7.80-7.74(m, 2H), 7.18- 7.09(m, 4H), 6.56 (d, J = 8.7 Hz, 2H), 3.87(s, 2H), 3.55(s, 2H), 3.02(t, J = 5.4 Hz, 2H). Ref. comp. 31

[M + H] = 341 ¹H NMR (300 MHz, CDCl₃) δ 7.70-7.62(m, 1H), 7.01 (d, J = 8.1 Hz, 2H), 6.92-6.76 (m, 2H), 6.52 (d, J = 8.1 Hz, 2H), 5.33 (s, 1H), 4.23(s, 2H), 3.77(m, 2H), 3.26 (m, 2H), 2.25(s, 3H). Ref. comp. 32

[M + H] = 229 ¹H NMR (300 MHz, DMSO-d₆) δ □8.83 (s, 1H), 8.30-8.28 (m, 1H), 7.89- 7.76 (m, 3H), 7.54-7.47 (m, 1H), 7.12-7.17 (m, 1H), 5.94 (s, 2H). Ref. comp. 33

[M + H] = 243.1 Ref. comp. 34

[M + H] = 452.2 Ref. comp. 35

[M + H] = 482 ¹H-NMR: (400 MHz, CD₃OD) δ 7.84-7.81 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.09-4.01 (m, 4H), 3.81 (t, J = 4.8 Hz, 2H), 1.89 (s, 6H), 1.46(s, 9H). Ref. comp. 36

[M + H] = 515.0 Ref. comp. 37

[M + H] = 452.2 Ref. comp. 38

[M + H] = 243 ¹H NMR: (300 MHz, DMSO-d₆) δ 8.79(d, J = 0.9 Hz, 1H), 8.26-8.24(m, 1H), 7.93-7.86(m, 1H), 7.85-7.83(m, 1H), 7.74(d, J = 4.8 Hz, 1H), 7.21(t, J = 9.3 Hz, 1H), 5.80(s, 2H), 2.29(d, J = 13.5 Hz, 3H Ref. comp. 39

[M + H] = 263 ¹H NMR (300 MHz, DMSO-d₆): δ 8.83(d, J = 1.2 Hz, 1H), 8.30-8.28(m, 1H), 8.18-8.15(m, 1H), 8.06-8.00(m, 1H), 7.78(d, J = 4.5 Hz, 1H), 7.51(d, J = 9 Hz, 1H), 5.91(s, 2H) Ref. comp. 40

[M + H] = 263 ¹H NMR-: (300 MHz, DMSO-d₆) δ 8.84(1H, d, J = 1.2 Hz), 8.30-8.28(1H, m), 7.99-7.88(2H, m), 7.77(1H, d, J = 4.8 Hz), 7.66(1H, t, J = 8.1 Hz), 6.01(2H, s) Ref. comp. 41

[M + H] = 260 ¹H NMR: (300 MHz, CDCl₃) δ 7.75-7.70(m, 2H), 7.10-7.03(m, 3H), 3.89(s, 2H), 3.78(s, 2H), 2.43(s, 3H), 1.19(s, 6H) Ref. comp. 42

[M + H] = 481.0 Ref. comp. 43

[M + H] = 445.0 Ref. comp. 44

¹H NMR: (400 MHz, CDCl₃) δ 7.88-7.92 (m, 2H), 7.07-7.11 (m, 2H), 4.88(s, 1H), 4.87(s, 2H), 3.84(s, 1H), 1.55(s, 6H), 1.51 (s, 6H), 1.37(s, 9H) Ref. comp. 45

[M + H] = 351.2 Ref. comp. 46

[M + H] = 338.0 Ref. comp. 47

[M + H] = 458.0 Ref. comp. 48

¹H NMR: (400 MHz, CDCl₃) δ 7.65-7.69 (m, 2H), 7.14 (s, 1H) 7.03 (t, J = 8.8 Hz, 2H), 4.62 (s, 2H), 3.11(s, 3H), 1.70(m, 6H) Ref. comp. 49

[M + H] = 481.1 Ref. comp. 50

¹H NMR: (400 MHz, CDCl₃) δ 7.87-7.90(m, 2H), 7.07 (t, J = 8.8 Hz, 2H), 3.86 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 1.50 (s, 6H) Ref. comp. 51

[M + H] = 232 ¹H NMR (300 MHz, DMSO-d₆) δ 4.47 (s, 2H), 4.65 (s, 2H), 7.15-7.21 (m, 2H), 7.55 (s, 1H), 7.74-7.79 (m, 2H), 8.48 (s, 1H) Ref. comp. 52

[M + H] = 277.0 ¹H NMR: (400 MHz, CD₃OD) δ 7.12-7.07(m, 2H), 4.95 (t, J = 2.0 Hz, 2H), 4.57 (t, J = 2.00 Hz, 2H). Ref. comp. 53

[M + H] = 306 ¹H NMR: (300 MHz, CDCl₃): δ 8.44-8.46(m, 2H), 7.79(m, 2H), 7.06-7.09(d, J = 8.1 Hz, 2H), 6.60-6.63 (d, J = 8.4 Hz, 2H), 5.57(s, 1H), 3.90(s, 2H), 3.81(m, 2H), 3.43(s, 1H), 3.03(m, 2H), 2.29(s, 3H) Ref. comp. 54

[M + H] = 335 ¹H NMR: (300 MHz, CDCl₃): δ 7.67 (d, J = 6 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 7.01 (t, J = 4.2 Hz, 2H), 6.94 (t, J = 8.1 Hz, 2H), 6.52 (d, J = 8.1 Hz, 2H), 5.87 (s, 1H), 4.20 (s, 2H), 3.83 (s, 3H), 3.75 (m, 2H), 3.49 (s, 1H), 3.22 (m, 2H), 2.24 (s, 3H) Ref. comp. 55

[M + H] = 338 ¹H NMR: (300 MHz, DMSO-d₆) δ 8.76(s, 1H), 7.94-7.89(m, 2H), 7.31-7.25(m, 2H), 4.57(s, 2H), 1.56(s, 6H). Ref. comp. 56

¹H NMR: (400 MHz, CD₃OD) δ 7.61-7.57(m, 2H), 7.16 (s, 1H); 7.00-6.96 (m, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.77 (t, J = 5.2 Hz, 2H), 1.76 (s, 6H), 1.42 (s, 9H) Ref. comp. 57

[M + H] = 302.2 Ref. comp. 58

[M + H] = 274 ¹H NMR: (300 MHz, CDCl₃): δ 7.73-7.78(m, 2H), 7.06-7.13(m, 3H), 6.73(s, 1H), 4.77(s, 2H), 4.72(s, 1H), 2.51-2.58(m, 1H), 1.09-1.12(d, J = 6.9 Hz, 3H), 0.87-0.91 (d, J = 6.9 Hz, 3H) Ref. comp. 59

[M + H] = 278 ¹H NMR: (300 MHz, CDCl₃): δ 7.60-7.64 (m, 1H), 7.42-7.60(m, 1H), 7.12-7.22 (m, 1H), 7.08 (s, 1H), 6.94 (s, 1H), 4.72 (s, 2H) Ref. comp. 60

¹H NMR: (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 7.75-7.79 (m, 2H), 7.54 (s, 1H), 7.16-7.22 (m, 2H), 4.62-4.73 (m, 3H), 1.51 (d, J = 6.3 Hz, 3H) Ref. comp. 61

[M + H] = 274 ¹H NMR (300 MHz, CDCl₃): δ 7.76-7.71(m, 2H), 7.12(m, 3H), 6.61(s, 1H), 4.71(s, 3H), 2.53-2.48(m, 1H), 1.11-1.08(m, 3H), 0.91-0.88(m, 3H). Ref. comp. 62

[M + H] = 246 ¹H NMR (300 MHz, DMSO-d₆): δ 8.60□ (s, 1H), 7.80-7.74 (m, 2H), 7.54 (s, 1H), 7.23-7.15 (m, 2H), 4.73-4.61 (m, 3H), 1.51 (d, J = 6.3 Hz, 3H,) Ref. comp. 63

[M + H] = 496 ¹H NMR (300 MHz, CDCl₃) 5.62-5.65(m, 1H), 5.39(s, 1H), 5.02-5.07(m, 1H), 4.62(m, 1H), 3.77-4.11(m, 6H), 3.35-3.39(m, 1H), 2.31(s, 1H), 1.47(s, 9H), 1.26-1.34(m, 3H), δ0.88-1.13(m, 3H), Ref. comp. 64

[M + H] = 467 ¹H NMR: (300 MHz, CDCl₃) δ 7.88-7.92 (t, J = 6.6 Hz, 2H), 7.10-7.15 (m, 2H), 5.41-5.51 (m, 1H), 5.02-5.19 (m, 2H), 4.05- 4.11 (m, 4H), 3.70-3.88 (m, 2H), 3.30 (m, 1H), 1.71-1.74 (m, 2H), 1.61-1.63 (m, 1H), 1.47 (s, 9H) Ref. comp. 65

[M + H] = 467 Ref. comp. 66

[M + H] = 496 ¹H NMR: (300 MHz, DMSO-d₆): δ 7.93-7.86(m, 2H), 7.31-7.25(m, 2H), 6.89 (s, 1H), 5.30-5.16 (m, 1H), 4.75-4.65 (m, 1H), 4.35- 4.26(m, 1H), 3.99-3.66(m, 4H), 2.28-2.15(m, 1H), 1.62-1.39(m, 10H), 1.01-0.88 (m, 3H). Ref. comp. 67

[M + H] = 338 ¹H NMR (300 MHz, DMSO-d₆) δ 8.76(s, 1H), 7.78(m, 1H), 7.65(m, 1H), 7.53- 7.45(m, 1H), 7.18-7.12(m, 1H), 4.58(s, 1H), 1.58(s, 6H) Ref. comp. 68

[M + H] = 345 ¹H NMR: (300 MHz, CDCl₃) δ 7.76-7.72 (m, 2H) 7.08-6.99 (m, 3H) 6.50-6.43 (m, H) 6.38-6.35 (m, 1H) 5.26 (s, H) 4.17 (s, 2H) 3.73-3.69 (m, 2H) 3.27-3.23 (m, 2H) 2.05 (s, 2H) Ref. comp. 69

[M + H] = 361 ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.28-7.38 (m, 2H), 6.94-7.00 (m, 1H), 6.42-6.52 (m, 2H), 3.88 (s, 2H), 3.57 (s, 2H), 3.04 (t, J = 5.1 Hz, 2H) Ref. comp. 70

[M + H] = 361 ¹H NMR: (400 MHz, CDCl₃) δ 7.75-7.70 (m, 2H) 7.25-7.19 (m, H), 7.05-7.02 (m, 2H), 6.48-6.41 (m, 2H), 4.16(s, 2H), 3.70 (m, 2H), 3.24 (m, 2H).

Reference Compound 1 N-(benzo[d][1,3]dioxol-5-yl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Reference Compound 1 was prepared in the following way:

A stirred solution of Compound 1-1 (685 mg, 10 mmol) in 10 mL of ethyl formate was heated to 120° C. for 2 hours in a microwave oven. Solvent was removed and the residue was subjected to MS-triggered HPLC purification to give 728 mg of Compound 1-2 as brown oil after neutralization. To a solution of Compound 1-2 (728 mg, 4.4 mmol) in 20 mL of DCM were added DIEA (2.30 mL, 13.2 mmol) and POCl₃ (0.45 mL, 4.84 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 2 hours and at room temperature for 2 additional hours. Solvent was removed and the residue was subjected to MS-triggered HPLC purification to give 281 mg of Compound 1-3 as yellow solid after neutralization: ¹H NMR (CDCl₃, 400 MHz) δ 6.88 (dd, J=2.0, 8.4 Hz, 1H), 6.79 (d, J=1.6 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.01 (s, 2H).

To a stirred solution of compound Compound 1-3 (158 mg, 1.66 mmol) in 10 mL of MeOH were added benzaldehyde (0.25 mL, 2.49 mmol), 2-aminopyrazine (281 mg, 1.91 mmol), and followed by 1.0 N HClO₄ in MeOH (0.17 mL, 0.17 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly taken to mass-triggered HPLC purification. The collected MeCN/water solution was concentrated and dried on a lyophilizer to give 296 mg of Compound 1-4 as powdery product: ¹H NMR (CDCl₃, 400 MHz) δ 9.23 (d, J=1.2 Hz, 1H), 8.03 (d, J=4.8 Hz, 1H), 7.91-7.94 (m, 3H), 7.26-7.44 (m, 3H), 6.68 (d, J=8.4 Hz, 1H), 6.32 (br, 1H), 6.25 (d, J=2.4 Hz, 1H), 6.00 (dd, J=2.4, 8.4 Hz, 1H), 5.93 (s, 2H).

To a stirred solution of Compound 1-4 (181 mg, 0.54 mmol) in 10 mL of MeOH was added Pd/C (58 mg, 0.054 mmol). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. 400 MHz proton NMR of the crude product proved it to be the title compound: ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (d, J=7.2 Hz, 2H), 7.91-7.94 (m, 3H), 7.21-7.27 (m, 3H), 6.59 (d, J=8.4 Hz, 1H), 6.26 (d, J=2.0 Hz, 1H), 5.99 (dd, J=2.0, 9.2 Hz, 1H), □□5.83 (s, 2H), 4.48 (s, 2H), 3.89 (s, 2H), 3.38 (s, 2H).

The following reference compounds were prepared by the same three component Ugi reaction used to prepare Reference Compound 1, using appropriate starting materials, followed by a Pd/C mediated hydrogenation: Reference Compound 2 was prepared from 2-aminopyridine, benzaldehyde and 1-isocyano-3,5-dimethylbenzene; Reference Compound 3 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and isocyanocyclopentane; Reference Compound 4 was prepared from 2-aminopyrazine, benzaldehyde and isocyanocyclopentane; Reference Compound 5 was prepared from 2-aminopyrazine, benzaldehyde and isocyanobenzene; Reference Compound 6 was prepared from 2-aminopyrazine, benzaldehyde and methyl 4-isocyanobenzoate; Reference Compound 7 was prepared from 2-aminopyrazine, 2-fluorobenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 8 was prepared from 2-aminopyrazine, benzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 9 was prepared from 2-aminopyrazine, 2,4,6-trifluorobenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 10 was prepared from 2-aminopyrazine, 3,5-difluorobenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 11 was prepared from 2-aminopyrazine, 4-pentylbenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 12 was prepared from 2-aminopyrazine, cyclohexanecarbaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 13 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and 3-isocyanopyridine; Reference Compound 14 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and isocyanocyclohexane; Reference Compound 15 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and 1-bromo-4-isocyanobenzene; Reference Compound 16 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and (isocyanomethyl)benzene; Reference Compound 17 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and isocyanofluoro)benzene; Reference Compound 22 was prepared from 2-aminopyrazine, 4-fluoro-2-hydroxy benzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 23 was prepared from 2-aminopyrazine, 4-methylbenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 24 was prepared from 2-aminopyrazine, 4-methoxybenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 25 was prepared from 2-aminopyrazine, 4-bromobenzaldehyde and 1-fluoro-4-isocyanobenzene; Reference Compound 26 was prepared from 2-aminopyrazine, 4-chlorobenzaldehyde and 1-fluoro-4-isocyanobenzene; and Reference Compound 29 was prepared from 2-aminopyrazine, 4-fluorobenzaldehyde and 1-methyl-4-isocyanobenzene.

Reference Compound 18 2,3-bis(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Reference Compound 18 was prepared by the following way:

To a solution of 2-(4-fluorophenyl)acetic acid (1.54 g, 10 mmol) in 30 mL dry DCM was added slowly SOCl₂ (2.18 mL, 30 mmol), 2 drops of DMF was added. The reaction mixture was stirred at reflux for 1 hour before the solvent was removed. The residue was dissolved in 30 mL of DCM and AlCl₃ (2.67 g, 22 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 10 mins. Fluorobenzene (0.94 mL, 10 mmol) in 2 mL of DCM was added dropwise at 0° C. The reaction mixture was allowed to stir at the same temperature for 2 hours. The reaction mixture was poured into a mixture of 30 mL of 0.1M HCl and 50 g crushed ice. The resulting mixture was separated and the aqueous layer was washed with DCM. The combined DCM solution was dried and concentrated. The residue was subjected to flash chromatography purification to give 983 mg of Compound 18-1 as light yellow solid: ¹H NMR (CDCl₃, 400 MHz) δ 8.04-8.08 (m, 2H), 7.23-7.26 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 7.04 (t, J=8.8 Hz, 2H), 4.26 (s, 2H).

To a solution of Compound 18-1 (232 mg, 1.0 mmol) in 6 mL of DCM was added Br₂ (61 μL, 1.2 mmol) in 12 mL of acetic acid. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was directly subjected to mass-triggered HPLC purification to give 181 mg yellow solid. The mass of the desired product on preparative HPLC was not right and did not show the characteristic peak pattern of bromides. The peak was collected by that mass and the compound was verified to be the right mass on the analytical HPLC, and also by 400 MHz proton NMR: ¹H NMR (CDCl₃, 400 MHz) δ 8.02-8.05 (m, 2H), 7.51-7.54 (m, 2H), 7.10-7.15 (m, 2H), 7.04-7.08 (m, 2H), 6.31 (s, 1H).

A solution of 2-aminopyrazine (57 mg, 0.60 mmol), Compound 18-2 (156 mg, 0.50 mmol) and K₂CO₃ (83 mg, 0.60 mmol) in 5 mL of EtOH was stirred at 120° C. for 3 hours. Solvent was removed and the residue was subjected to MS-triggered HPLC purification. The collected MeCN/water solution was neutralized. The organic solution was dried and concentrated to give Compound 18-3 as yellow oil: ¹H NMR (CDCl₃, 400 MHz) δ 9.14 (d, J=1.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 2H), 7.62-7.65 (m, 2H), 7.42-7.45 (m, 2H), 7.28 (t, J=8.4 Hz, 2H), 7.02 (t, J=8.8 Hz, 2H), 6.31 (s, 1H).

To a stirred solution of Compound 18-3 (10 mg, 0.033 mmol) in 6 mL of MeOH was added Pd/C (4 mg, 0.0033 mmol). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. The product was subjected to mass-triggered HPLC purification to give the title compound as yellow oil after neutralization.

Reference Compound 19 2-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3-amine

Reference Compound 19 was prepared by the following way:

To a stirred solution of 2-aminopyrazine (571 mg, 6.0 mmol) in 10 mL of MeOH were added 4-fluorobenzaldehyde (0.97 mL, 9.0 mmol), 2-isocyano-2-methylpropane (0.78 mL, 6.9 mmol), and followed by 1.0 N HClO₄ in MeOH (0.60 mL, 0.60 mmol). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed and the residue was subjected to flash chromatography purification to give Compound 19-1 as white solid: ¹H NMR (CDCl₃, 400 MHz) δ 8.97 (d, J=1.6 Hz, 1H), 8.10 (dd, J=1.6, 4.4 Hz, 1H), 7.90-7.94 (m, 2H), 7.13 (t, J=8.8 Hz, 2H), 1.04 (s, 9H).

A solution of Compound 19-1 (284 mg, 1.0 mmol) in 10 mL of 4:1 DCM and TFA was stirred at room temperature for 2 hours. Solvent was removed and the product was directly used in the next step after neutralization.

Reference Compound 20 N-(3-fluorophenyl)-2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Reference Compound 20 was prepared by the following way: to a solution of Reference Compound 19 (69 mg, 0.30 mmol) in 6 mL of dioxane were added 1-bromo-3-fluorobenzene (66 μL, 0.60 mmol), Pd₂(dba)₃ (8 mg, 0.009 mmol), Xantphos (11 mg, 0.018 mmol) and Cs₂CO₃ (196 mg, 0.60 mmol) at room temperature. The reaction mixture was degassed and stirred at 120° C. under N₂ for 5 hours. The reaction mixture was cooled to room temperature and solid was filtered off. The resulting filtrate was concentrated. The residue was subjected to mass-triggered HPLC purification to give a yellow oil after neutralization. To a stirred solution of the obtained adduct (64 mg, 0.20 mmol) in 5 mL of MeOH was added Pd/C (21 mg, 0.02 mmol). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give a yellow solid.

Reference Compound 27 was prepared from Reference Compound 19 by an amination reaction with 1-bromo-3,5-difluorobenzene followed by a Pd/C mediated hydrogenation; Reference Compound 28 was prepared from Reference Compound 19 by an amination reaction with 1-bromo-4-(trifluoromethyl)benzene followed by a Pd/C mediated hydrogenation; Reference Compound 30 was prepared from Reference Compound 19 by an amination reaction with 1-bromo-4-(trifluoromethyl)benzene followed by a Pd/C mediated hydrogenation; Reference Compound 31 was prepared from Reference Compound 11 by an amination reaction with 1-bromo-2,4-difluorobenzene followed by a Pd/C mediated hydrogenation; Reference Compound 32 was prepared by the same way that Reference Compound 19 was prepared: a three component Ugi reaction among 2-aminopyrazine, 3-fluorobenzaldehyde and 2-isocyano-2-methylpropane followed by a TFA mediated deprotection; Reference Compound 34 was prepared by a three component Ugi reaction among 2-aminopyrazine, 3-fluorobenzaldehyde, and 2-isocyano-2-methylpropane followed by a HATU mediated amidation reaction with 2-(benzyloxycarbonylamino)-2-methylpropanoic acid and HCl mediated deprotection.

Reference Compound 33 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyrazin-3-amine

Reference Compound 33 was prepared by the same way that Reference Compound 1 was prepared:

To a stirred solution of 5-bromopyrazin-2-amine (313 mg, 1.8 mmol) in 20 mL of MeOH were added 4-fluorobenzaldehyde (191 μL, 1.8 mmol), and followed by 1.0 N HClO₄ in MeOH (0.15 mL, 0.15 mmol). The reaction mixture was stirred at room temperature for 0.5 hour which was followed by addition of 2-isocyano-2-methylpropane (170 μL, 1.5 mmol). The stirring was continued at room temperature overnight. The reaction mixture was subjected to direct mass-triggered HPLC purification to give 299 mg of Compound 33-1 as a yellow solid.

To a stirred solution of Compound 33-1 (131 mg, 0.36 mmol) in 10 mL of dioxane were added 2.0 M Me₂Zn in toluene (0.75 mL, 1.5 mmol) and Ni(DPPP)₂Cl₂ (98 mg, 0.18 mmol). The reaction mixture was evacuated and back filled with N₂. The reaction mixture was stirred at reflux overnight. Reaction mixture was quenched with methanol. Solid was filtered off and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give Compound 33-2 as yellow oil.

To a solution of Compound 33-2 (9 mg, 0.03 mmol) in 2 mL of DCM was added 4 mL of TFA. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was subjected to mass-triggered HPLC purification to give the titled compound in quantitative yield after neutralization.

Reference Compound 35 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyrazin-3-amine

Reference Compound 35 was prepared by the following way:

To a solution of 2-bromo-1-(4-fluorophenyl)ethanone (46.5 g, 214.29 mmol) in DMF (400 mL), were added 2-(benzyloxycarbonyl)-2-methylpropanoic acid (55.8 g, 236.4 mmol) and potassium carbonate (35.4 g, 256.5 mmol). The resulting solution was stirred for 4 h at room temperature. The resulting solution was diluted with 1000 mL of water. The resulting solution was extracted with ethyl acetate (2×800 mL) and the combined organic layer was washed with water (2×800 mL), brine (1×800 mL). The resulting mixture was concentrated under vacuum. This resulted in 67 g (84%) of Compound 35-1 as a white solid.

To a solution of Compound 35-1 (70 g, 187.7 mmol) in toluene (700 mL), was added NH₄OAc (144.5 g, 1.88 mol). The resulting solution was heated to reflux for 3 h in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 800 mL of water. The resulting solution was extracted with ethyl acetate (2×500 mL) and the combined organic layer was washed with water (2×800 mL) and brine (1×800 mL). The resulting mixture was concentrated under vacuum. This resulted in 58 g (88%) of Compound 35-2 as a white solid.

To a solution of Compound 35-2 (58 g, 164.3 mmol) in DMF (400 mL), were added cesium carbonate (134 g, 411.0 mmol). This was followed by the addition of ethyl 2-bromoacetate (33 g, 197.6 mmol) dropwise with stirring at room temperature in 30 min. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 1000 mL of water/ice. The resulting solution was extracted with ethyl acetate (2×700 mL) and the combined organic layer was washed with water (2×800 mL) and brine (1×800 mL). The resulting mixture was concentrated under vacuum. This resulted in 60 g (83%) of Compound 35-3 as a yellow solid.

To a solution of Compound 35-3 (70 g, 159.4 mmol) in methanol (800 mL), was added 10% Pd/C (10 g). The resulting solution was degassed and back filled with hydrogen. The solution was stirred for 3 days at 35° C. The solids were filtered out. The filtrate was concentrated under reduced pressure. This resulted in Compound 35-4 as a white solid: ¹H NMR: (DMSO, 300 MHz): δ 7.79-7.74 (m, 2H), 7.13-7.07 (m, 3H), 6.35 (s, 2H), 4.73 (s, 2H), 1.79 (s, 6H)

To a stirred solution of Compound 40-4 (15 g, 57.9 mmol) in THF (300 mL) was added of BH₃ Me₂S complex (144.2 mL, 2M) dropwise at room temperature in 30 min. The resulting solution was reflux for 4 h. After cooling to room temperature, the resulting solution was diluted with 100 mL of methanol. The pH was adjusted to 1-2 with hydrochloric acid (12N). The mixture was reflux for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of water. pH was adjusted to 9-10 with aqueous potassium carbonate (40%). The resulting solution was extracted with 3×200 mL of DCM and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in Compound 35-5 as a white solid.

To a stirred solution of Compound 35-5 (7.3 g, 29.8 mmol) in DMF (150 mL) was added N-Boc-glycine (17 g, 89.4 mmol), followed by HATU (37.2 g, 122 mmol) & DIEA (25.3 g, 178 mmol). The resulting solution was stirred for 3 h at room temperature. The resulting mixture diluted with 600 mL of ethyl acetate, washed with saturated aqueous NaHCO₃ (30 mL×6), brine (30 mL×3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. This resulted in crude product, which was triturated and sonicated with ether (20 mL×3) to give Compound 35-6: ¹H NMR (300 MHz, DMSO-d₆) δ7.77-7.72 (m, 2H), 7.54 (s, 1H), 7.20-7.14 (m, 2H), 6.84-6.80 (m, 1H), 4.07 (s, 2H), 3.90 (d, J=3 Hz, 2H), 3.70 (s, 2H), 1.80 (s, 6H), 1.40 (s, 9H).

To a stirred solution of Compound 35-6 (3.02 g, 7.51 mmol) in 30 mL of DCM was added Br₂ (0.43 mL, 8.26 mmol) in 3 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. HPLC/MS test showed that desired product (II) was the only peak. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, 3.76 g white solid was obtained. The product was confirmed by 400 MHz proton NMR to be the title compound. The product was used in the next step without further purifications.

Reference Compound 36 was prepared by a similar way that Reference Compound 35 was made except that N-Cbz-glycine was used in step (f). Reference Compound 37 was prepared by a three component Ugi reaction among 2-aminopyrazine, 4-fluorobenzaldehyde, and 2-isocyano-2-methylpropane followed by a HATU mediated amidation reaction with 2-(benzyloxycarbonylamino)-2-methylpropanoic acid and a HCl mediated deprotection. Reference Compound 38 was prepared in the same way that Reference Compound 19, by a three component Ugi reaction among 2-aminopyrazine, 4-fluoro-3-methylbenzaldehyde, and 2-isocyano-2-methylpropane followed by a TFA mediated deprotection. Similarly, Reference Compound 39 was prepared from Reference Compound 19 by a three component Ugi reaction among 2-aminopyrazine, 3-chloro-4-fluorobenzaldehyde, and 2-isocyano-2-methylpropane followed by a TFA mediated deprotection. Reference Compound 40 was prepared by the same way that Reference Compound 19 was prepared: a three component Ugi reaction among 2-aminopyrazine, 4-chloro-3-fluorobenzaldehyde, and 2-isocyano-2-methylpropane followed by a TFA mediated deprotection.

Reference Compound 41 2-(4-fluorophenyl)-6,6,7-trimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Reference Compound 41 was prepared from Compound 42-2 by the following way:

To a stirred solution of Compound 42-2 (500 mg, 2.04 mmol, 1.00 equiv) in CH₃CN (10 mL) was added formalin (5 mL). The reaction mixture was stirred at RT for 20 min, which were followed by addition of NaBH₃CN (400 mg, 6.35 mmol, 3.00 equiv) and acetic acid (1 mL, 1.00 equiv). The reaction mixture was allowed to stir for an additional 1 h at room temperature. Sodium hydroxide (1N aqueous) was added to neutralize the mixture. The solution was extracted with ethyl acetate (3×10 ml) and the combined organic layer was washed with brine (3×10 mL), dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (40:1). This resulted in the title compound as a light-yellow solid.

Reference Compound 42 tert-butyl 2-(3-bromo-2-(4-fluorophenyl)-6,6-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethylcarbamate

Reference Compound 42 was prepared from Compound 51-2 by the following way:

To a stirred solution of Compound 51-2 (1.1 g, 3.38 mmol, 1.00 equiv) in DMF (30 mL) was added 3-chloro-2-methylprop-1-ene (500 mg, 5.49 mmol, 1.50 equiv), potassium carbonate (560 mg, 4.06 mmol, 1.10 equiv) and KI (1.12 g, 6.75 mmol, 2.00 equiv) at room temperature. The reaction mixture was stirred for 48 h at 40° C. The reaction mixture was diluted with 100 ml of ethyl acetate. The mixture was washed with brine (3×10 mL), dried over sodium sulfate, concentrated under vacuum. The residue was applied onto a silica gel column with Petroleum Ether/EtOAc (5:1) to give Compound 42-1 as a light yellow solid.

Into a 30-mL sealed tube, was placed Compound 42-1 (2.0 g, 5.28 mmol, 1.00 equiv), AcOH (12 mL), MsOH (2 mL). The reaction mixture was stirred for 12 h at 260° C. (the temperature of the sand bath). The reaction mixture was cooled to room temperature. The mixture was poured into 20 ml of water. The aqueous layer was washed with ethyl acetate (3×10 mL). Aqueous sodium hydroxide (1N) was added to adjust pH to 8. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 ml), dried over sodium sulfate, concentrated under vacuum. The solid was collected by filtration and washed with 5 mL of n-hexane to give Compound 42-2 as a white solid.

To a stirred solution of Compound 42-2 (280 mg, 1.14 mmol, 1.00 equiv) in DMF (10 mL) was added 2-(tert-butoxycarbonyl)acetic acid (600 mg, 3.43 mmol, 3.00 equiv), HATU (1.3 g, 3.42 mmol, 3.00 equiv) and DIEA (880 mg, 6.82 mmol, 6.00 equiv) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate. The organic layer was washed with brine (3×10 mL), dried over sodium sulfate, concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10:1) to give Compound 42-3 as a brown solid: ¹H NMR: (300 MHz, CDCl₃) δ 7.72-7.68 (m, 2H), 7.23 (s, 1H), 7.13-7.07 (m, 2H), 5.46 (s, 1H), 4.65 (s, 2H), 4.05-4.04 (m, 2H), 3.97 (s, 2H), 1.55-1.39 (m, 15H).

To a stirred solution of Compound 42-3 (386 g, 0.96 mmol) in 6 mL of DCM was added Br₂ (55 μL, 1.06 mmol) in 2 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was subjected to flash chromatography (40 g, 0-100% ethyl acetate in hexane, 50 mins, dry loading) purification to give the title compound as a colorless oil.

Reference Compound 43 3-bromo-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,5-dimethyl-5,6,7,8-tetra hydroimidazo[1,2-a]pyrazine

Reference Compound 43 was prepared from Compound 51-2 by the following way:

To a solution of Compound 43-1 (231 mg, 1.0 mmol) in 10 mL of DMF were added KOH (168 mg, 3.0 mmol), and PMBCl (405 μL, 3.0 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 2 hours and at room temperature for 2 additional hours. The reaction mixture was directly taken to LC/MS purification to give Compound 43-2 as white solid after neutralization.

To a solution of Compound 43-2 (253 mg, 0.72 mmol) in 15 mL of DMF were added 60% NaH (87 mg, 0.085 mmol), and MeI (0.45 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with methanol and directly subjected to mass-triggered HPLC purification to give mg of Compound 43-3 as a white solid after neutralization: ¹H-NMR: (400 MHz, CDCl₃) δ 7.47-7.49 (m, 1H), 7.41-7.45 (m, 1H), 7.28-7.32 (m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.88-6.93 (m, 1H), 6.86 (d, J=8.8 Hz, 2H), 4.67 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 1.75 (s, 6H).

To a solution of Compound 43-3 (170 mg, 0.45 mmol) in 9 mL of THF was added 1.0 N BH₃.THF (2.70 mL, 2.70 mmol) at room temperature. The reaction mixture was stirred at reflux for 2 hours. Pd/C was added (gas generated). The reaction mixture was stirred for 1 hour. Solid was filtered off and solvent was removed. The crude Compound 43-4 was directly tested with 400 MHz proton NMR to prove that the product was the right one. The product was assumed to be of 100% yield and used in the next step without further purifications.

To a stirred solution of Compound 43-4 (164 g, 0.45 mmol) in 6 mL of DCM was added Br₂ (26 μL, 0.50 mmol) in 2 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was subjected to ISCO (24 g, 0-100% ethyl acetate in hexane, 25 mins, dry loading) purification to give the title compound as white solid.

Reference Compound 44 tert-butyl 1-(3-bromo-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydro imidazo[1,2-a]pyrazin-7(8H)-yl)-2-methyl-1-oxopropan-2-ylcarbamate

Reference Compound 44 was prepared from Compound 40-5 by the following way:

To a stirred solution of Compound 35-5 (1.48 g, 6.04 mmol) and NEt₃ (6.0 g, 59.4 mmol) in DCM (20 mL) was added 2-bromo-2-methylpropanoyl bromide (14 g, 60.9 mmol) dropwise at room temperature. After being stirred for 3 h at room temperature, the reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in crude product as a dark solid, which was washed with EtOAc: Petroleum Ether (1:10) to remove the impurities to produce Compound 44-1 as a gray solid.

To a solution of Compound 44-1 (2.0 g, 5.08 mmol, 1.00 equiv) in DMF (10 mL) was NaN₃ (1.0 g, 15.38 mmol, 3.00 equiv) at r.t. The reaction mixture was stirred overnight at room temperature. The resulting solution was diluted with 300 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with Petroleum Ether/EtOAc (5:1) to give Compound 44-2 as a white solid.

To a stirred solution of Compound 44-2 (1.2 g, 3.37 mmol, 1.00 equiv) in methanol (20 mL) was added Pd/C (80 mg, 0.75 mmol, 0.20 equiv) at room temperature. The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The solid was washed with Petroleum Ether. This resulted in Compound 44-3 as a white solid.

To a stirred solution of Compound 44-3 (910 mg, 2.76 mmol, 1.00 equiv) in THF (50 mL) was added BOC anhydride (3.2 g, 14.68 mmol, 5.00 equiv), followed by aqueous NaOH (1N, 6 ml, 2.00 equiv) at rt. The resulting solution was stirred for 24 h at 40° C. The resulting solution was concentrated under vacuum. The mixture was diluted with 60 ml of EtOAc. The organic layer was washed with 3×10 ml of brine, dried over Na₂SO₄, concentrated under vacuum. The solid was collected by filtration and washed with n-hexane (5 ml) to give Compound 44-4 as a white solid: ¹H-NMR: (300 MHz, CDCl₃) δ 7.75-7.71 (m, 2H), 7.09-7.02 (m, 3H), 4.84 (s, 1H), 4.09-4.0 (m, 4H), 1.98 (s, 6H), 1.55 (s, 6H), 1.45 (s, 9H).

To a stirred solution of Compound 44-4 (32 mg, 0.074 mmol) in 3 mL of DCM was added Br₂ (4.2 μL, 0.082 mmol) in 1 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was subjected to flash chromatography (4 g, 0-60% ethyl acetate in hexane, 16 mins) purification to give the title compound as colorless oil.

Reference Compound 45 2-(3-fluorophenyl)-5,5-dimethyl-N-p-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Reference Compound 45 was prepared from Reference Compound 43 in the following way: To a solution of Reference Compound 43 (116 mg, 0.26 mmol) in 8 mL of dioxane were added 4-methylaniline (84 mg, 0.78 mmol), Pd₂(dba)₃ (24 mg, 0.026 mmol), XantPhos (30 mg, 0.052 mmol) and Cs₂CO₃ (169 mg, 0.52 mmol) at room temperature. The reaction mixture was degassed and stirred at 150° C. under N₂ for 6 hours. Solid was filtered off and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give 116 mg yellow solid as TFA salt. A solution of the adduct (108 mg, 0.23 mmol) in 2 mL of TFA was stirred at 70° C. for 90 mins in a microwave oven. HPLC test showed that the starting material was gone and the desired product was the major peak. TFA was removed and the residue was directly subjected to flash chromatography purification (12 g, 0-10% methanol in DCM with NH₃ modification, 30 mins) to give the title compound as clear oil.

Reference Compound 46 was prepared from Compound 43-4 by a TFA mediated deprotection followed by alkylation. Reference Compound 47 was prepared in the same way that Compound 48-3 was made followed by bromination (except that Reference Compound 51 was used in step (a)).

Reference Compound 48 2-(4-fluorophenyl)-5,5,7-trimethyl-7,8-dihydroimidazo[1,2-a]pyrazine-6(5H)-one

Reference Compound 48 was prepared from Reference Compound 51 by the following way: To a solution of Reference Compound 51 (694 mg, 3.0 mmol) in 20 mL of DMF were added 60% NaH (600 mg, 15 mmol), and MeI (1.87 mL, 30 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 2 hours and at room temperature for 2 additional hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic solution was dried and concentrated to give the methylated product white solid after flash chromatography purification: ¹H NMR: (400 MHz, CDCl₃) δ 7.65-7.69 (m, 2H), 7.14 (s, 1H) 7.03 (t, J=8.8 Hz, 2H), 4.62 (s, 2H), 3.11 (s, 3H), 1.70 (m, 6H).

To a stirred solution of (I) (216 mg, 0.79 mmol) in 6 mL of DCM was added Br₂ (45 μL, 0.87 mmol) in 2 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was used in the next step without further purifications.

Reference Compound 49 tert-butyl 2-(3-bromo-2-(3-fluorophenyl)-5,5-dimethyl-5,6-dihydro imidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethylcarbamate

Reference Compound 49 was prepared from Compound 43-4 by the following way:

A solution of (I) (365 mg, 1.0 mmol) in 10 mL of TFA was stirred at 70° C. for 20 mins. HPLC test showed that the starting material was remaining and small amount desired product was detected. The reaction mixture was stirred at 75° C. for 30 mins in a microwave oven. TFA was removed and the residue neutralized to give about 252 mg of Compound 49-1 (100%) as yellow oil.

To a stirred solution of Compound 49-1 (245 mg, 1.0 mmol) and N-Boc-glycine (350 mg, 2.0 mmol) in 10 mL of DMF were added HATU (760 mg, 2.0 mmol) and DIEA (0.52 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 hours

The reaction mixture diluted with ethyl acetate and washed with water. The organic solution was dried and concentrated. The residue was subjected to flash chromatography purification (24 g, 0-100% ethyl acetate in hexane, 36 mins) to give Compound 49-2 as clear oil.

To a stirred solution of Compound 49-2 (312 mg, 0.78 mmol) in 6 mL of DCM was added Br₂ (57 μL, 1.1 mmol) in 2 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was subjected to flash chromatography (25 g, 0-100% ethyl acetate in hexane, 32 mins, dry loading) purification to give the title compound as colorless oil.

Reference Compound 50 3-bromo-2-(4-fluorophenyl)-7,8,8-trimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Reference Compound 50 was prepared from Compound 35-5 by the following way:

To a stirred solution of Compound 35-5 (2.4 g, 9.80 mmol, 1.00 equiv) in CH₃CN (50 ml) was added formalin (1.71 g, 21.09 mmol, 2.00 equiv, 37%). The mixture was stirred at 30° C. for 30 minutes. To this was added NaCNBH₃ (1.85 g, 29.37 mmol, 3.00 equiv), acetic acid (590 mg, 9.83 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 ml of water. The pH value of the solution was adjusted to 8-9 with sodium carbonate (saturated). The resulting solution was extracted with DCM (3×100 ml) and the combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:7) to give Compound 50-1 as a white solid: ¹H NMR: (300 MHz, CDCl₃) δ 7.69-7.75 (m, 2H), 7.02-7.09 (t, J=9 Hz, 2H), 6.97 (s, 1H), 4.01-4.06 (t, J=5.4 Hz, 2H), 3.02-3.07 (t, J=5.4 Hz, 2H), 2.49 (s, 3H), 1.52-1.57 (m, 6H).

To a stirred solution of Compound 50-1 (933 mg, 3.60 mmol) in 6 mL of DCM was added Br₂ (204 μL, 3.96 mmol) in 2 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was subjected to flash chromatography (40 g, 0-10% methanol in DCM, 50 mins, dry loading) purification to give 998 mg (82%) of the title compound as white solid.

Reference Compound 51 2-(4-fluorophenyl)-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one

Reference Compound 51 was prepared by the following way:

To a stirred solution of 2-bromo-1-(4-fluorophenyl)ethanone (3.0 g, 13.82 mmol) in DMF (30 mL) was added 2-(tert-butoxycarbonyl)acetic acid (2.5 g, 14.29 mmol) and Cs₂CO₃ (5.0 g, 15.34 mmol). The resulting solution was allowed to stir overnight at 30° C. The resulting solution was poured into 40 ml of water. The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organic layer was washed with brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The solid was washed with a mixture of n-hexane/ethyl acetate (10:1). This resulted in Compound 51-1 as a white solid.

To a stirred solution of Compound 51-1 (25.95 g, 75.14 mmol) in toluene (200 mL), was added NH₄OAc (110 g, 20.00 equiv). The resulting solution was heated to reflux for 4 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with 800 mL of ethyl acetate. The resulting mixture was washed with brine (3×30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed with 10 mL of Petroleum Ether/EtOAc (20:1) to give Compound 51-2 as a white solid.

To a stirred solution of Compound 51-2 (2.58 g, 8.87 mmol) in DMF (30 mL) was added ethyl 2-bromoacetate (4.4 g, 26.35 mmol, 3.00 equiv) and Cs₂CO₃ (8.7 g, 26.69 mmol, 3.00 equiv). The resulting solution was stirred overnight at 30° C. The resulting solution was diluted with 30 mL of ethyl acetate and the combined organic layer was washed with brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in Compound 51-3 as a light white solid.

To a stirred solution of Compound 51-3 (8 g, 19.46 mmol) in methanol (200 mL), was added Pd/C (0.8 g). The resulting solution was degassed and back filled with hydrogen. The mixture was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting crude solid was washed with 100 mL of Petroleum Ether/EtOAc (1:10). This resulted in the title compound as a white solid.

Reference Compound 52 was prepared from Reference Compound 51 by nitrating with fuming nitric acid in TFA. Reference Compound 53 was prepared in the same way that Reference Compound 19 was prepared: a three component Ugi reaction among 2-aminopyrazine, isonicotinaldehyde, and 2-isocyano-2-methylpropane followed by a TFA mediated deprotection. The free amine was subjected to Pd₂(dba)₃ mediated amination reaction with 1-bromo-4-methylbenzene followed by a PtO₂ mediated hydrogenation. Reference Compound 54 was prepared from 2-aminopyrazine, 2-methoxybenzaldehyde, 1-isocyano-4-methylbenzene by the same three component Ugi reaction to prepare Reference Compound 1, and then followed by a PtO₂ mediated hydrogenation.

Reference Compound 55 3-bromo-2-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one

Reference Compound 55 was prepared from Compound 35-4 in the following way: To a stirred solution of Compound 35-4 (390 mg, 1.51 mmol, 1.00 equiv) in DCM (20 mL) was added NBS (0.28 g, 1.00 equiv). The resulting solution was stirred for 2 hours at room temperature. The solid was filtered out and the mixture was washed with a saturated solution of Na₂S₂O₃, dried over Na₂SO₄. The mixture was concentrated under vacuum. The solids was purified by silica gel chromatography (Petroleum Ether/EtOAc=1:2) to result in the title compound as a white solid.

Reference Compound 56 was prepared from Compound 35-5 by reacting with Boc-OSu in THF at 50° C. Reference Compound 57 was prepared from Compound 35-4 by alkylation using NaHi MeI. Reference Compound 58 was prepared by the same way that Compound 35-4 except that (R)-2-(benzyloxycarbonyl)-3-methylbutanoic acid was used in step (a). Reference Compound 59 was prepared in the same way that compound 35-4 except that 2-bromo-1-(3,4-difluorophenyl)ethanone was used in step (a). Reference Compound 60 was prepared by the same way that Compound 35-4 was made except that (S)-2-(benzyloxycarbonyl)propanoic acid was used in step (a). Reference Compound 61 was prepared by the same way that Compound 35-4 was made except that (S)-2-(benzyloxycarbonyl) 3-methylbutanoic acid was used in step (a). Reference Compound 62 was prepared by the same way that Compound 35-4 was made except that (R)-2-(benzyloxycarbonyl)propanoic acid was used in step (a). Reference Compound 63 was prepared from by the same method that Reference Compound 35 was prepared except that (S)-2-(benzyloxycarbonyl)-3-methylbutanoic acid was used in step (a). Reference Compound 64 was prepared from by the same method that Reference Compound 35 was prepared except that (R)-2-(benzyloxycarbonyl)-3-methylbutanoic acid was used in step (a). Reference Compound 65 was prepared from by the same method that Reference Compound 35 was prepared except that (S)-2-(benzyloxycarbonyl)-3-methylbutanoic acid was used in step (a). Reference Compound 66 was prepared from by the same method that Reference Compound 35 was prepared except that (R)-2-(benzyloxycarbonyl)-3-methylbutanoic acid was used in step (a). Reference Compound 67 was prepared in the same way that Reference Compound 55 was made except that 2-bromo-1-(3-fluorophenyl)ethanone was used in step (a). Reference Compound 68 was prepared from Reference Compound 19 by an amination reaction with 1-bromo-2,4-difluorobenzene followed by a Pd/C mediated hydrogenation. Reference Compound 69 was synthesized from Reference Compound 32 was prepared from an amination reaction with 1-bromo-3-fluoro-4-chlorobenzene followed by a PtO₂ mediated hydrogenation. Reference Compound 70 was synthesized from Reference Compound 11 was prepared from an amination reaction with 1-bromo-3-fluoro-4-chlorobenzene followed by a PtO₂ mediated hydrogenation. Reference Compound 71 was synthesized from Reference Compound 51 in a similar way as Reference Compound 49 was prepared.

Reference Compound 72 3-bromo-7-(2-(dimethylamino)ethyl)-2-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one

Reference Compound 72 was prepared from Compound 35-4 by the following reaction:

To a solution of Compound 35-4 (259 mg, 1.0 mmol) in 5 mL of DMF were added 60% NaH (60 mg, 1.5 mmol, and 2-bromo-N,N-dimethylethanamine (228 mg, 1.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. LC/MS test showed that Compound 35-4 was gone and the desired product ([M+1]=331 was one the major peaks.

The reaction mixture was diluted with ethyl acetate and washed with water twice. The organic solution was dried and concentrated. The obtained crude product was used in the next step without further purifications.

To a stirred solution of crude product obtained from the previous step (198 mg, 0.60 mmol) in 3 mL of DCM was added Br₂ (34 μL, 0.66 mmol) in 1 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 minutes. HPLC/MS test showed that starting material gone and Reference Compound 72 was the major product.

Solvent was removed via rotavap at a temperature no higher than 20° C. The residue was subjected to a mass-triggered HPLC purification to give 110 mg of Reference Compound 72.

Reference Compound 73: 3-(4-fluoro-3-methylphenylamino)-2-(3-fluorophenyl)-8,8-dimethyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one was synthesized from Reference Compound 67 by a Pd₂(dba)₃ mediated amination reaction with 4-fluoro-3-methylaniline. Reference Compound 74: tert-butyl 3-bromo-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydro imidazo[1,2-a]pyrazine-7(8H)-carboxylate was prepared from Reference Compound 56 by a bromination reaction with Br₂. Reference Compound 75: 2-bromo-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone was prepared from Example 493 by an amidate reaction with 2-bromoacetyl bromide.

Reference Compound 76 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-amine

Reference Compound 76 was prepared by the following steps:

To a stirred solution of 5-methylpyridin-2-amine (260 mg, 2.4 mmol) in 20 mL of MeOH was added 4-fluorobenzaldehyde (0.26 mL, 2.40 mmol), and followed by 1.0 N HClO₄ in MeOH (0.20 mL, 0.20 mmol). The reaction mixture was stirred at room temperature for 0.5 hour which was followed by addition of 2-isocyano-2-methylpropane (0.23 mL, 2.0 mmol). The stirring was continued at room temperature overnight. HPLC/MS test showed that the desired product Reference Compound 76-1 was a major peak.

The reaction mixture was subjected to direct mass-triggered HPLC purification. The obtained 62 mg of the Ugi adduct as yellow solid.

To a solution of the Ugi adduct (366 mg, 1.23 mmol) in 5 mL of DCM was added 5 mL of TFA. The reaction mixture was stirred at room temperature. LC/MS test showed a major peak with [M+1]=338, which corresponded to Reference Compound 76-2. The reaction mixture was concentrated to give 431 mg yellow solid.

To a solution of Reference Compound 76-2 (101 mg, 0.30 mmol) in 3 mL of MeOH and 3 mL of water was added KOH (168 mg, 3.0 mmol). The reaction mixture was stirred at 60° C. for 3 hours. LC/MS test showed a major peak with [M+1]=242, which corresponded to the desired product of Reference Compound 76. The reaction mixture was concentrated and the residue was dissolved in DCM. The organic solution is washed with NaHCO₃, dried and concentrated. The product was used without further purifications.

Reference Compound 77: 2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-amine was prepared by the same steps as Reference Compound 76.

Physical Data Compound Structure MS (m/z) and/or ¹H NMR Ref. comp. 71

[M + 1] = 481 ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 7.2 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.67- 4.82 (m, 2H), 4.05 (s, 2H), 3.55-3.78 (m, 2H), 1.71 (s, 3H), 1.67 (s, 3H), 1.41 (s, 9H) Ref. comp. 72

[M + 1] = 409 ¹H NMR (400 MHz, CD₃OD): δ 7.61-7.65 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.23-7.26 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.26 (s, 2H), 4.15 (s, 2H), 4.11 (s, 2H), 3.88 (s, 2H), 2.08 (s, 6H) Ref. comp. 73

[M + 1] = 383 Ref. comp. 74

[M + 1] = 424 ¹H NMR (400 MHz, CDCl₃): δ 7.87-7.90 (m, 2H), 7.08 (t, J = 8.8 Hz, 2H), 3.88-3.94 (m, 4H), 1.85 (s, 6H), 1.53 (s, 9H) Ref. comp. 75

[M + 1] = 475 Ref. comp. 76

[M + 1] = 242 Ref. comp. 77

[M + 1] = 228 ¹H NMR (400 MHz, CDCl₃): δ 7.94-7.80 (m, 3H), 7.52 (dt, J = 1.2, 9.2 Hz, 1H), 7.10-7.15 (m, 3H), 6.81 (dt, J = 1.2, 6.8 Hz, 1H), 3.33 (br, 2H)

Example 1 2-amino-1-(3-(benzo[d][1,3]dioxol-5-ylamino)-2-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 1 was prepared in the following way: to a stirred solution of N-BOC-glycine (142 mg, 0.81 mmol) in 2 mL of DMF were added HATU (308 mg, 0.81 mmol) and DIEA (0.28 mL, 1.62 mmol). After stirring for 10 minutes, Reference Compound 1 (180 mg, 0.54 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours.

Solvent was removed and the crude product was subjected to MS-triggered HPLC purification. The collected MeCN/water solution was concentrated till no more MeCN was left. The remaining aqueous solution was neutralized with NaHCO₃ and extracted with DCM. The organic solution was dried and concentrated. The residue was dissolved in 1:1 MeCN/water solvent, dried on a lyophilizer to give 192 mg powdery product.

A solution of the above obtained amide (265 mg, 0.54 mmol) in 10 mL of 4:1 DCM and TFA was stirred at room temperature for 2 hours. Solvent was removed and the crude product was subjected to MS-triggered HPLC purification. The collected MeCN/water solution was concentrated till no more MeCN was left. The remaining aqueous solution was neutralized with NaHCO₃ and extracted with DCM. The organic solution was dried and concentrated. Then was dissolved in 1:1 MeCN/water solvent, dried on lyophilizer to give powdery product.

Example 26

N,2-bis(4-fluorophenyl)imidazo[1,2-a]pyrazin-3-amine

Example 26 was synthesized by the following way: to a stirred solution of 2-aminopyrazine (683 mg, 7.18 mmol) in 50 mL of MeOH were added 4-fluorobenzaldehyde (1.16 mL, 10.8 mmol), 1-fluoro-4-isocyanobenzene (1.0 g, 8.25 mmol), and followed by 1.0 N HClO₄ in MeOH (0.72 mL, 0.72 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was subjected to flash chromatography purification. The collected organic solution was concentrated to give the title compound as yellow oil.

Example 28 N,2-bis(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Example 28 was synthesized by the following way: to a stirred solution of Example 26 (761 mg, 2.36 mmol) in 10 mL of MeOH was added Pd/C (258 mg, 0.24 mmol). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. The product was subjected to mass-triggered HPLC purification. The obtained MeCN/water solution was combined and concentrated to give the final product as yellow oil after neutralization.

Example 29 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one

Example 29 was synthesized by the following way: To a stirred solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (25 mg, 0.12 mmol) in 2 mL of DMF were added HATU (46 mg, 0.12 mmol) and DIEA (63 μL, 0.36 mmol). After stirring for 10 minutes, Example 331(21 mg, 0.06 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly subjected to a mass-triggered HPLC purification. The collected MeCN/water solution was concentrated and neutralized. The obtained product (26 mg, 0.05 mmol) in 5 mL of 4:1 DCM and TFA was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was subjected to mass-trigger HPLC purification. The collected MeCN/water solution was combined and MeCN was removed.

Example 32 1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(methylamino)ethanone

Example 32 was prepared from Example 28 by the following way:

Example 28 (33 mg, 0.10 mmol) in 10 mL of DCM were added Et₃N (84 μL, 0.60 mmol) and 2-chloroacetyl chloride (24 μL, 0.30 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 2 hours and at room temperature for 2 additional hours. Solvent was removed and the residue was subjected to MS-triggered HPLC purification to give 40 mg of Compound 32-1 as yellow solid (100%) after neutralization: ¹H NMR (CDCl₃, 400 MHz) δ 7.63-7.66 (m, 2H), 6.99 (t, J=8.8 Hz, 2H), 6.90 (t, J=8.4 Hz, 2H), 6.60-6.63 (m, 2H), 4.97-5.14 (m, 2H), 4.13-4.21 (m, 2H), 4.03 (d, J=3.2 Hz, 2H), 3.91 (s, 2H).

Compound 32-1 (20 mg, 0.05 mmol) in 5 mL of DMF were added K₂CO₃ (21 mg, 0.15 mmol) and 2.0 M MeNH₂ (0.30 mL, 0.60 mmol) at room temperature. The reaction mixture was stirred at the same temperature overnight. Solvent was removed and the residue was subjected to MS-triggered HPLC purification to give the title compound as yellow solid after neutralization.

Example 44 1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-hydroxyethanone

Example 44 was synthesized by the following way: to a solution of Compound 32-1 (20 mg, 0.05 mmol) in 5 mL of DMF were added KI (8 mg, 0.05 mmol) and AcOK (15 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at the same temperature overnight. Solvent was removed and the residue was subjected to MS-triggered HPLC purification to give yellow solid. A solution of the solid (21 mg, 0.05 mmol) in 3 mL of methanol and 1 mL of water was added LiOH (6 mg, 0.25 mmol). The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature and organic solvent was removed. The residue was taken to mass triggered HPLC separation. The collected MeCN/water solution was concentrated to give the title compound as yellowish oil.

Example 113 2-(4-fluorophenyl)-N-p-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Example 113 was prepared by the following way: to a stirred solution of the Example 136 (64 mg, 0.20 mmol) in 5 mL of MeOH was added Pd/C (21 mg, 0.02 mmol). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give a yellow solid.

Example 136 2-(4-fluorophenyl)-N-p-tolylimidazo[1,2-a]pyrazin-3-amine

Example 136 was prepared by the following way: to a solution of Reference Compound 19 (69 mg, 0.30 mmol) in 6 mL of dioxane were added 4-bromotoluene (74 μL, 0.60 mmol), Pd₂(dba)₃ (8 mg, 0.009 mmol), Xantphos (11 mg, 0.018 mmol) and Cs₂CO₃ (196 mg, 0.60 mmol) at room temperature. The reaction mixture was degassed and stirred at 120° C. under N₂ for 5 hours. The reaction mixture was cooled to room temperature and solid was filtered off. The resulting filtrate was concentrated. The residue was subjected to mass-triggered HPLC purification to give about 72 mg of the title compound as yellow oil (75%) after neutralization.

Example 251 (3-(dimethylamino)pyrrolidin-1-yl)(2-(4-fluorophenyl)-3-(p-tolylamino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methanone

Example 251 was prepared from Example 113 by the following way:

To a stirred solution of Example 113 (161 mg, 0.50 mmol) and Et₃N (139 μL, 1.5 mmol) in 10 mL of DCM were added 4-nitrophenyl carbonochloridate (202 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to MS-triggered HPLC separation. The collected MeCN/water solution was combined and concentrated to give Compound 251-1 as yellow oil: ¹H NMR: (300 MHz, DMSO-d₆) δ8.34-8.31 (m, 3H) 7.80-7.75 (m, 2H) 7.54 (m, 2H) 7.35-7.29 (m, 1H) 7.20-7.14 (m, 2H) 6.60-6.50 (m, 2H) 4.93 (s, 1H) 4.74 (s, 1H) 4.07 (s, 1H) 3.92 (s, 1H) 3.81 (m, 2H).

Compound 251-1 (20 mg, 0.041 mmol) and Et₃N (17 μL, 0.123 mmol) in 2 mL of NMP were added N,N-dimethylpyrrolidin-3-amine (15 μL, 0.123 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to MS-triggered HPLC purification. The collected MeCN/water solution was combined and concentrated to give the title compound as yellow oil.

Example 262 N-(4-chlorophenyl)-2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-mine

Example 262: was prepared by the following way: to a solution of Reference Compound 19 (69 mg, 0.30 mmol) in 6 mL of dioxane were added 1-bromo-4-chlorobenzene (115 mg, 0.60 mmol), Pd₂(dba)₃ (8 mg, 0.009 mmol), Xantphos (11 mg, 0.018 mmol) and Cs₂CO₃ (196 mg, 0.60 mmol) at room temperature. The reaction mixture was degassed and stirred at 120° C. under N₂ for 5 hours. The reaction mixture was cooled to room temperature and solid was filtered off. The resulting filtrate was concentrated. The residue was subjected to mass-triggered HPLC purification to give a yellow oil after neutralization. To a stirred solution of the obtained adduct (68 mg, 0.20 mmol) in 5 mL of MeOH was added Pd/C (21 mg, 0.02 mmol). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give 39 mg (57%) of the title compound as yellow solid.

Example 266 2-m-tolyl-N-p-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Example 266 was synthesized by the following way: to a 100-mL round-bottom flask, was placed a solution of pyrazin-2-amine (1.2 g, 12.6 mmol), 3-methylbenzaldehyde (1.44 g, 12.0 mmol) and HClO₄ (200 mg, 2.0 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, then to the mixture was added 1-isocyano-4-methylbenzene (1.2 g, 10.3 mmol). The resulting solution was allowed to stir for 12 hr at room temperature. After removing the solvent, the residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to result 1.1 μg the Ugi adduct. To a solution of the obtained Ugi adduct (1.0 g, 3.18 mmol) in methanol (50 mL) was added PtO₂ (72 mg, 0.32 mmol). Then the reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at RT overnight. The solid was filtered out and the filtrate was concentrated under vacuum to result in the title compound as a white solid.

Example 267 (S)-tert-butyl 1-(2-(4-fluorophenyl)-3-(p-tolylamino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-1-oxo-3-(4-(pentylamino)phenyl)propan-2-ylcarbamate

Example 267 was synthesized from Example 113 by a HATU mediated coupling with (S)-2-(tert-butoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid followed by Pd/C mediated hydrogenation for the aniline derivative. To a stirred solution of aniline derivative (33 mg, 0.056 mmol) in 5 mL of dry THF was added pentanal (18 μL, 0.168 mmol) under nitrogen at room temperature. NaBH₄ (6 mg, 0.168 mmol) was added after 30 mins. The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed. The residue was dissolved in methanol and subjected to mass-triggered HPLC purification. The obtained MeCN/water solution was combined and concentrated to give yellow oil.

Example 289 (5R,8R)-2,8-dibenzyl-3-methyl-5-phenethyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one

Example 289 was prepared in the following way:

To a stirred solution of (R)-2-(benzyloxycarbonylamino)-3-phenylpropanoic acid (5 gm, 1.0 eq.) and (R)-ethyl 2-amino-3-phenylpropanoate hydrochloride (3.83 gm, 1.0 eq.) in 30 mL of DMF were added HATU (6.98 gm, 1.1 eq.) and DIEA (3.44 ml, 1.1 eq.). The reaction mixture was stirred at room temperature for 6 hours. HPLC/MS test showed that desired product Compound 289-1 was the only product, but was contaminated with other peak. The reaction was partitioned between EtOAc/water and then crude was purified with flash chromatography to give Compound 289-1.

To a stirred solution of Compound 289-1 (3 gm, 1.0 eq.) and 9.5 ml of 2 N NaOH and 30 ml THF were mixed. The reaction mixture was stirred at room temperature for 6 hours. The reaction was acidified and then partitioned between EtOAc/water and then crude was as such in the next step.

To a stirred solution of Compound 289-2 (1 gm, 1.0 eq.) and acetic anhydride (0.254 ml, 1.2 eq.) in dichloromethane (25 ml) were added DIEA (0.756 ml, 4.4 eq.)) and DMAP (13.4 mg, 5 m %). The reaction mixture was stirred at room temp. for 8 hrs. LCMS indicated that the desired product was formed. The organic layer was quenched with MeOH and concentrated. The organic layer was washed with water/EtOAc and used as crude in next step.

Compound 289-3 (0.8 gm, 1.0 eq.) and (R)-ethyl 2-amino-4-phenylbutanoate (0.596 gm, 1.6 eq.) were mixed along with PTSA (10 m %). The reaction was heated to 130° C. in a Dean-Stark apparatus. Slight vacuum was applied from the top to get vigorous reflux. The reaction was heated for 2 hrs. Toluene was removed from the side arm and the volume was replenished in the main vessel 3-4 times to drive the reaction to completion. LCMS indicated completion of reaction as indicated by formation of new peak. The new peak had no mass. The reaction was concentrated and crude was subjected to next step.

Compound 289-4 was dissolved in pyridine and POCl₃ was added the reaction was stirred for 48 hrs. LCMS indicated that desired product was formed. The reaction was concentrated. The oil was neutralized with sat. NaHCO₃. and extracted with dichloromethane. The organic layer was dried/concentrated and subjected to column chromatography.

To a stirred solution of Compound 289-5 (0.7 g, 1.0 eq.) in 30 mL of MeOH was added Pd/C (0.007 g). The reaction mixture was evacuated and back filled with H₂. The reaction mixture was stirred at room temperature overnight. HPLC test showed that the starting material is all gone and (II) was the major peak. Solid was filtered off and solvent was removed to give the title compound. LCMS indicated that the reaction had racemized (2 peaks).

Example 292 N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-5,6,7,8-tetrahydro imidazo[1,2-a]pyrazin-3-amine

Example 292 was prepared by the following way: to a stirred solution of pyrazin-2-amine (2.4 g, 25.26 mmol) in 20 ml of MeOH, were added 4-fluorobenzaldehyde (3.0 g, 24.19 mmol), and HClO₄ (70%, 0.4 g), then the mixture was stirred at room temperature for 30 min which was followed by addition of 1-chloro-2-fluoro-4-isocyanobenzene (3.2 g, 20.58 mmol). The stirring was continued at room temperature overnight, Then the solvent was removed in vacuo, and the crude product was purified by silica gel chromatography with dichloromethane/methanol to yield the Ugi adduct as a yellow solid.

To a solution of the obtained Ugi adduct (1.2 g, 3.36 mmol, 1.00 equiv) in DMF (10 mL) was added sodium hydride (1.0 g, 25.00 mmol, 1.20 equiv, 60%) at 0° C. The reaction mixture was stirred at this temperature for 30 mins, which was followed by addition of iodomethane (1.7 g, 11.97 mmol, 3.56 equiv). The resulting solution was allowed to react, with stirring, for 30 min at 0° C. The reaction mixture was poured into 20 ml of ice water. The solid was collected by filtration and washed with 10 ml of water to result in 1.1 g (88%) of the N-methyl product.

To a solution of the N-methyl product (1.0 g, 2.70 mmol, 1.00 equiv) in methanol (100 mL) was added PtO₂ (30 mg, 0.13 mmol, 0.10 equiv). The resulting solution was allowed to react, with stirring, for 8 hr at room temperature. The solids were filtrated out, and the resulting solution was concentrated under vacuum. The residue was applied onto silica gel chromatography with dichloromethane/methanol (20:1) to result in 500 mg (49%) of the title compound as a white solid.

Example 297 N-tert-butyl-2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Example 297 was synthesized from the precursor of Reference Compound 19-1 by the following way: to a solution of Reference Compound 19-1 (1.0 g, 3.52 mmol, 1.00 equiv) in methanol (20 mL), was added PtO₂ (80 mg, 0.35 mmol, 0.10 equiv). The resulting solution was evacuated and back filled with hydrogen, and the stirring was continued at room temperature overnight. The solid was filtered off and the solvent was evaporated under vacuum. The residue was applied to silica gel chromatography with dichloromethane/methanol (50:1) to give 837 mg (83.7%) of the title compound as a white solid.

Example 412 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 412 was prepared from Reference Compound 35 by a Pd₂(dba)₃ mediated amination reaction with p-toluidine follo107wed by a TFA mediated deprotection.

Synthesis of Reference Compound 35-4

To a stirred solution of Reference Compound 35-3 (70 g, 159.45 mmol, 1.00 equiv.) in methanol (800 mL) was added Palladium on carbon (10 g). The resulting solution was degassed and back filled with hydrogen. The solution was stirred for 3 days at 25° C. The solids were filtered out and washed with MeOH. The filtrate was concentrated under reduced pressure. This resulted in Reference Compound 35-4 (38 g, 145.56 mmol, 91%) of as a white solid. LC-MS: (ES, m/z): [M+H]⁺ calculated for C₁₄H₁₄FN₃O, 260. found 260. H-NMR: (DMSO, 300 Hz) δ7.79-7.74 (2H, m), 7.13-7.07 (3H, m), 6.35 (H, s), 4.73 (2H, s), 1.79 (6H, s).

Synthesis of Reference Compound 35-5

Reference Compound 35-4 (5 g, 19.2 mmol, 1 equiv.) was dissolved in 50 mL of THF, 1M Borane/THF complex (57 ml, 57 mmol, 3 equiv.) was added slowly and reaction was refluxed overnight. LCMS indicated that the reaction was complete. THF was removed under reduced pressure. The reaction was quenched with MeOH. The crude product of Reference Compound 35-5 (4.5 g, 18.3 mmol, 95%) was used in the next step. LC-MS: (ES, m/z): [M+H]⁺ calcd for C₁₄H₁₇FN₃ 246. found 246. H-NMR: (DMSO, 300 Hz) δ7.75-7.70 (2H, m), 7.4 (s, 1H), 7.14 (2H, J=9 Hz, t), 3.9 (2H, J=5.4 Hz, t), 2.51 (2H, J=5.4 Hz, t), 1.41 (6H, s).

Synthesis of Reference Compound 35-6

To a stirred solution of Reference Compound 35-5 (2.9 g, 11.82 mmol, 1.1 equiv.) and 2-(tert-butoxycarbonylamino)acetic acid (2.27 g, 13 mmol, 1.1 equiv.) in 15 mL of dichloromethane were added DIEA (2.47 ml, 14.18 mmol, 1.2 equiv.), HATU (5.39 gm, 14.18 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 8 hours. HPLC/MS analysis showed that desired product Reference Compound 35-6 was the major product. The reaction was diluted 70 ml dichloromethane. The organic layer was washed with washed with water (1×30 ml), followed by saturate NaHCO₃ (1×30 ml) and finally with brine (1×30 ml). The organic layer was then dried over anhydrous Na₂SO₄, and concentrated in vacuo. The resulting oil was purified using column chromatography with hexanes/ethyl acetate (0-100% linear gradient) used as eluant. The desired product Reference Compound 35-6 was obtained as an oil (3.3 g, 8.27 mmol, 70%). ¹H NMR: (300 Hz, DMSO-d₆) δ7.77˜7.72 (2H, m), 7.54 (1H, s), 7.20˜7.14 (2H, m), 6.84˜6.80 (1H, m), 4.07 (2H, s), 3.90 (2H, d, J=3 Hz), 3.70 (2H, s), 1.80 (6H, s), 1.40 (9H, s). LC-MS: (ES, m/z): [M+H]⁺ calcd for C₂₁H₂₈FN₄O₃403. found 403.

Synthesis of Reference Compound 36

To a solution of Reference Compound 35-6 (2.0 g, 4.97 mmol, 1.00 equiv.) in MeCN (20 mL) was added NBS (0.88 g, 1.00 equiv). The resulting solution was stirred for 15 minutes at room temperature. HPLC/MS indicated that the desired product Reference Compound 36 was formed exclusively. The reaction was evaporated under reduced pressure. The solids were dissolved in 50 ml dichloromethane. The organic layer was then dried over anhydrous Na₂SO₄, and concentrated in vacuo. The resulting solids were purified with column chromatography using hexanes/ethyl acetate (0-100%) as eluant. The desired compound Reference Compound 36 was obtained as an off white/glassy solid (1.9 g, 3.96 mmol, 80%). LC-MS: (ES, m/z): [M+H]⁺ calcd for C₂₁H₂₇BrFN₄O₃482 found 482. H-NMR: (MeOH-d₄, 400 Hz) δ7.84-7.81 (2H, m), 7.14 (2H, J=8.8 Hz, t), 4.09-4.01 (4H, m), 3.81 (2H, J=4.8 Hz, t),1.89 (6H, s), 1.46 (9H, s).

Synthesis of Example 412

In a glass vial, Cs₂CO₃ 4F-aniline (0.462 g, 4.1 mmol, 2.0 equiv.), Pd₂(dba)₃ (0.095 g, 0.104 mmol, 0.05 equiv.), Xantphos (0.120 g, 0.208 mmol, 0.1 equiv.) and dioxane were stirred for 5 minutes at room temperature. Reference Compound 36 (1 g, 2.08 mmol, 1.0 equiv.) was added to the reaction mixture after which the reaction mixture was degassed for 15 mins and then stirred at 120° C. under N₂ for 8 hours. HPLC/MS test showed that the starting material Reference Compound 36 was consumed and desired product was formed predominantly along with some Reference Compound 35-6. The reaction was filtered to remove solids. The reaction mixture was concentrated and then purified by normal phase column chromatography (silicagel 80 gm) using a gradient of 100%-0 to 0-100% hexane: EtOAc. The desired product elutes at 60:40 EtOAc:hexanes. The organic layer was concentrated at reduced pressure to yield the Boc derivative (950 mg, 89.3%) yield. LC-MS: (ES, m/z): [M+H]⁺ calcd for C₂₇H₃₂F₂N₅O₃512. found 512.

The Boc-compound was treated with 20% TFA in CH₂Cl₂ (50 ml) was the reaction was stirred for 4 hours.) was added to the mixture. After the completion of this reaction (monitored by LCMS), the resulting mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to yield product as a TFA salt. The ACN-water layer was concentrated to remove all the solvents. The residue was dissolved in dichloromethane and carefully neutralized by sat. NaHCO₃. The organic layer was successively washed with brine followed by water. The organic layer was concentrated to yield Example 412 (450 mg, 52% for 2 steps). LC-MS: (ES, m/z): [M+H]⁺ calcd for C₂₂H₂₃F₂N₅O 412. found 412. H-NMR: (MeOH-d₄, 400 Hz) δ7.61-7.57 (2H, m), 6.94 (2H, J=8.8 Hz, t), 6.81 (2H, J=8.8 Hz, t), 6.47 (2H, m), 3.72 (2H, m), 3.58 (2H, m), 3.42 (2H, m), 1.85 (6H, s). Elemental Analysis: (Example 412 with 0.65 equiv. H₂O): C, 62.44; N, 16.55; H, 5.79, (calculated). C=62.54/62.44; N=16.35/16.29; H=5.52/5.61 (experimental).

Example 417 2-amino-1-(3-(4-chlorophenylamino)-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 417 was prepared from Reference Compound 36 by a Pd₂(dba)₃ mediated amination reaction with 4-chloroaniline followed by a 6N HCl mediated deprotection.

Example 331 N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Example 331 was synthesized from Reference Compound 19 by the following way: to a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Reference Compound 19 (1.5 g, 6.12 mmol) and 4-bromo-1,2-difluorobenzene (2.4 g, 12.44 mmol) in 1,4-dioxane (100 mL) were added Pd₂(dba)₃ (170 mg, 0.19 mmol), X-Phos (175 mg, 0.37 mmol) and Cs₂CO₃ (4 g, 12.28 mmol) under nitrogen. The resulting solution was heated to 120° C. and stirred overnight. The solids were filtrated out and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to result in 1.9 g (87%) of diaryl amine as a brown solid.

To a solution of the obtained diaryl amine (1.9 g, 5.33 mmol) in methanol (50 mL) was added PtO₂ (130 mg, 0.57 mmol). The mixture was degassed and backed filled with hydrogen. The resulting solution was allowed to react, with stirring, overnight at room temperature. The solids were filtrated and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (50:1) to result in the title compound as a brown solid.

Example 529 2-amino-1-(2-(4-fluorophenyl)-8,8-dimethyl-3-(p-tolylamino)-5,6-dihydro imidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one

Example 529 was prepared from Example 415 by the following way:

To a stirred solution of Example 415 (21 mg, 0.06 mmol) and Et₃N (83 μL, 0.60 mmol) in 6 mL of dry DCM was added 2-bromo-2-methylpropanoyl bromide (71 μL, 0.60 mmol). The reaction mixture was stirred at room temperature for 5 hour. The reaction mixture was concentrated and subjected to mass-triggered LC/MS purification directly. The obtained solutions were concentrated to give 22 mg (73%) of Compound 529-1 as yellow oil after neutralization.

To a solution of Compound 529-1 (22 mg, 0.044 mmol) in 3 mL of DMF was added NaN₃ (8.6 mg, 0.132 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was directly subjected to mass-triggered LC/MS purification directly. The obtained MeCN/aqueous solution was combined and concentrated to give 15 mg (75%) of Compound 529-2 as yellow oil after neutralization.

To a solution of Compound 529-2 (15 mg, 0.033 mmol) in 3 mL of MeOH was added 10% Pd/C (4 mg, 0.003 mmol) at room temperature. Air was removed and H₂ was filled. The reaction mixture was stirred at room temperature for 2 hours. Solid was filtered off and solvent was removed. The reaction mixture was directly subjected to mass-triggered HPLC purification to give 15 mg (100%) of the title compound yellow oil.

Example 530 tert-butyl 1-(2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methyl-1-oxopropan-2-ylcarbamate

Example 530 was prepared from Compound 540-1 by the following way:

To a stirred solution of Compound 540-1 (1.0 g, 4.61 mmol, 1.00 equiv) in DMF (20 mL) was added 2-(tert-butoxycarbonyl)-2-methylpropanoic acid (1.12 g, 5.52 mmol, 1.20 equiv), EDC (1.06 g, 5.52 mmol, 1.20 equiv), HOBT (1.8 g, 13.24 mmol, 2.87 equiv), DIEA (1.78 g, 13.80 mmol, 2.99 equiv). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with ethyl acetate (2×150 mL) and the organic combined layer was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:2˜1). This resulted in the title compound as a yellow solid.

Example 540 tert-butyl 2-(2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethylcarbamate

Example 540 was prepared from Reference Compound 51 by the following way:

To a stirred solution of Reference Compound 51 (4.2 g, 18.18 mmol, 1.00 equiv) in THF (150 mL) was added BH₃Me₂S (45 mL, 2M) dropwise at room temperature in 10 mins. The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of methanol. The pH value of the solution was adjusted to 1 with conc. HCl, and the mixture was refluxed for 1 hr. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of water. Potassium carbonate was employed to adjust the pH to 10. The resulting solution was extracted with THF (4×200 mL) and the combined organic layer was washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3 g (76%) of Compound 540-1 as a white solid.

To a stirred solution of Compound 540-1 (1.0 g, 4.61 mmol, 1.00 equiv) in DMF (20 mL) was added 2-(tert-butoxycarbonyl)acetic acid (1.2 g, 6.86 mmol, 1.49 equiv) and HATU (5.2 g, 13.68 mmol, 2.97 equiv). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 300 mg (17%) of the title compound as a white solid.

Example 556 N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6,7-trimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine

Example 556 was prepared from Reference Compound 41 bromination followed by a Pd₂(dba)₃ mediated amination reaction with 4-chloroaniline. The bromination procedure is shown below:

To a stirred solution of Compound 41-1 (52 mg, 0.20 mmol) in 6 mL of DCM was added Br₂ (11.3 μL, 0.22 mmol) in 2 mL of acetic acid. The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed via rotavap at a temperature no higher than 20° C. After neutralization, the residue was subjected to flash chromatography (40 g, 0-10% methanol in DCM, 50 mins, dry loading) purification to give 59 mg (87%) of the title compound as white solid.

Example 645 8-(3,4-difluorophenylamino)-9-(4-fluorophenyl)-2,2-dimethyl-5,6-dihydrodiimidazo[1,2-a:2′,1′-c]pyrazin-3(2H)-one

Example 645 was prepared from Example 29 by the following method: to a stirred solution of Example 29 (12 mg, 0.03 mmol) was added MnO₂ (52 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC/MS test showed that Example 29 was almost gone and the desired product ([M+1]=526) was detected as one of the major peaks. Solid was filtered off and solvent was removed. The residue was subjected to a mass-triggered HPLC purification to give Example 645.

Example 646 8-(3,4-difluorophenylamino)-9-(4-fluorophenyl)-2,2-dimethyl-1,2,5,6-tetrahydrodiimidazo[1,2-a:2′,1′-c]pyrazin-3(10bH)-one

Example 646 was prepared from Example 29 by the following method: to a stirred solution of Example 29 (12 mg, 0.03 mmol) was added MnO₂ (52 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC/MS test showed that Example 29 was almost gone and the desired product ([M+1]=528) was detected as one of the major peaks. Solid was filtered off and solvent was removed. The residue was subjected to a mass-triggered HPLC purification to give Example 646.

Example 687 7-(2-aminoethyl)-2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one

Example 687 was prepared from Example 688 by the following steps:

To a stirred solution of Example 688 (22 mg, 0.05 mmol) and Et₃N (42 μL, 0.30 mmol) in 3 mL of DCM were added MsCl (12 μL, 0.15 mmol). The reaction mixture was stirred at room temperature for 3 hours. HPLC/MS test showed that Example 688 was all gone and the desired product ([M+1]=519) was formed as the only major peak. Solvent was removed and the residue was subjected to a mass-triggered HPLC purification to give 18 mg of mesylate. To a stirred solution of the mesylate (5 mg, 0.01 mmol) in 2 mL of MeOH was added 1 mL of 5 M in MeOH. The reaction mixture was stirred at 120° C. for 20 minutes in a microwave oven. HPLC/MS test showed that the mesylate was all gone and Example 687 ([M+1]=440) was formed as the one of the major peaks. Solvent was removed and the residue was subjected to a mass-triggered HPLC purification to give 3 mg of Example 687.

Example 692 4-(3-(4-fluoro-3-methylphenylamino)-2-(3-fluorophenyl)-8,8-dimethyl-6-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)butanoic acid

Example 692 was prepared from Reference Compound 73 by the following steps:

To a solution of Reference Compound 73 (10 mg, 0.03 mmol) in 3 mL of DMF were added KOH (8 mg, 0.12 mmol), and ethyl 4-bromobutanoate (24 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred in a microwave oven at 90° C. for 20 minutes. LC/MS test showed that 50% of starting material was remaining and the desired product ester ([M+1]=497) was the major product. The reaction mixture was filtered and subjected to mass-triggered HPLC purification to give the ester as colorless oil. The obtained ester was hydrolyzed by LiOH to give Example 692.

Example 695 2-amino-1-(2-(4-fluorophenyl)-3-(4-methoxybenzyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 695 was prepared from Reference Compound 74 by the following steps:

To a solution of Reference Compound 74 (21 mg, 0.05 mmol) in 3 mL of dry THF was added 2.5 N (0.025 mL, 0.06 mmol) at −78° C. The reaction mixture was stirred at the same temperature for 20 mins and (II) (41 mg, 0.30 mmol) in 1 mL of dry THF was added. The reaction mixture was stirred for another 5 hours while the temperature raised to room temperature. LC/MS test showed that starting material was all gone and the desired adduct Example 695-1 (20 mg, 84%) was isolated as the major product.

To a solution of Example 695-1 (10 mg, 0.021 mmol) in 3 mL of i-PrOH were added 10% Pd/C (3 mg, 0.004 mmol) and 1,4-cyclohexadiene (20 μL, 0.21 mmol). The reaction mixture was stirred at 120° C. for 3 hours in a Q-tube. LC/MS test showed that the starting material was gone and there was a major peak with [M+1]=466, which corresponded to the desired product. Solid was filtered off and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give 16 mg of crude Example 695-2 as brown oil. Example 695-2 was subjected to a TFA mediated deprotection to get 3 mg of Example 695-3 ([M+1]=366).

To a stirred solution of Example 695-3 (4 mg, 0.01 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (5.2 mg, 0.03 mmol) in 2 mL of DMF were added HATU (12 mg, 0.03 mmol) and DIEA (5.2 VL, 0.03 mmol). The reaction mixture was stirred at room temperature for 3 hours. LC/MS test showed that the starting material was almost gone and the desired adduct ([M+1]=523) was formed as the one of the major peaks. The reaction subjected to a mass-triggered HPLC purification to give the adduct, which was subjected to a TFA mediated deprotection to get 6 mg of Example 695 ([M+1]=422).

Example 700 2-amino-1-(2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-p-tolylpropan-1-one

Example 700 was prepared from Reference Compound 35 by the following steps:

To a solution of Reference Compound 35 (48 mg, 0.10 mmol) in 3 mL of dry THF was added 2.2 N n-BuLi (0.11 mL, 0.24 mmol) at −78° C. The reaction mixture was stirred at the same temperature for 20 minutes and 1-(bromomethyl)-4-methylbenzene (111 mg, 0.60 mmol) in 1 mL of dry THF was added. The reaction mixture was stirred for another 5 hours while the temperature raised to room temperature. LC/MS test showed that starting material was all gone and adduct. The reaction mixture was quenched with NH₄Cl aqueous solution and diluted with ethyl acetate. The organic solution was separated, dried and concentrated. The residue was subjected to a mass-triggered HPLC purification to give 28 mg of the adduct as clear oil. This was subjected to a TFA mediated deprotection to give Example 700.

Example 704 2-amino-1-(2-(4-fluorophenyl)-8,8-dimethyl-3-p-tolyl-5,6-dihydroimidazo-[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 704 was prepared from Reference Compound 35 in the following steps:

Reference Compound 35 (48 mg, 0.10 mmol), p-tolylboronic acid (27 mg, 0.20 mmol), Pd(PPh₃)₄(12 mg, 0.01 mmol), and 1.0 N Na₂CO₃ (0.20 mL, 0.20 mmol) were combine in a 40 mL vial. 5 mL of THF was added. The reaction mixture was de-gassed by repeated evacuation and re-fill with nitrogen. And the reaction mixture was stirred at 70° C. for 2 hours. LC/MS test showed that Reference Compound 35 was almost gone and the desired adduct was detected as one of the major peaks. Solid was filtered and solvent was removed. The residue was subjected to a mass-triggered HPLC purification to give 22 mg of the desired adduct. This was subjected to a TFA mediated deprotection to give Example 704.

Example 707 N,2-bis(4-fluorophenyl)-8,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

Example 707 was prepared from Reference Compound 74 by the following steps:

To a solution of Reference Compound 74 (21 mg, 0.05 mmol) in 3 mL of dry THF was added 2.5 N n-BuLi (0.04 mL, 0.10 mmol) at −78° C. The reaction mixture was stirred at the same temperature for 20 mins and 1-fluoro-4-isocyanatobenzene (33 μL, 0.30 mmol) in 1 mL of dry THF was added. The reaction mixture was stirred for another 5 hours while the temperature raised to room temperature. LC/MS test showed that starting material was all gone and the desired adduct was detected as a major peak. Solid was filtered and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give 56 mg of the desired adduct as brown oil. The adduct was subjected to a TFA mediated deprotection to get 22 mg of Example 707 ([M+1]=393) as yellow solid.

Example 709 2-amino-1-(3-(4-fluorophenoxy(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 709 was prepared from Reference Compound 35 in the following steps:

To a solution of Reference Compound 35 (48 mg, 0.10 mmol) in 5 mL of dioxane were added 4-fluorophenol (34 mg, 0.30 mmol), CuI (3.8 mg, 0.02 mmol), N,N-dimethylglycine (4.1 mg, 0.04 mmol) and Cs₂CO₃ (98 mg, 0.30 mmol) at room temperature. The reaction mixture was degassed and stirred at 120° C. under N₂ overnight. LC/MS test showed that the starting material was all gone and the desired adduct ([M+1]=513) was detected as a major peak. Solid was filtered and solvent was removed. The residue was subjected to a mass-triggered HPLC purification to give 28 mg of the desired adduct. This was deprotected with TFA to give Example 709.

Example 713 2-amino-1-(2-(4-fluorophenyl)-8,8-dimethyl-3-(p-tolylthio)-5,6-dihydro imidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 713 was prepared from Reference Compound 35 in the following steps:

To a solution of Reference Compound 35 (24 mg, 0.05 mmol) in 3 mL of dioxane were added 4-methylbenzenethiol (17 mg, 0.15 mmol), Pd₂(dba)₃ (9.2 mg, 0.01 mmol), XantPhos (12 mg, 0.02 mmol) and Cs₂CO₃ (33 mg, 0.10 mmol) at room temperature. The reaction mixture was degassed and stirred at 150° C. under N₂ overnight. LC/MS test showed that about 50% of the starting material was remaining and the desired adduct was one of the major peaks ([M+1]=525). Solid was filtered and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give 32 mg of the adduct as brown oil. This was deprotected with TFA to give Example 713.

Example 721 2-amino-1-(2-(4-fluorophenyl)-8,8-dimethyl-3-(p-tolylsulfinyl)-5,6-dihydro imidazo[1,2-a]pyrazin-7(8H)-yl)ethanone

Example 721 was prepared from Reference Compound 35 in the following steps:\

To a solution of Reference Compound 35 (24 mg, 0.05 mmol) in 3 mL of dioxane were added 4-methylbenzenethiol (17 mg, 0.15 mmol), Pd₂(dba)₃ (9.2 mg, 0.01 mmol), XantPhos (12 mg, 0.02 mmol) and Cs₂CO₃ (33 mg, 0.10 mmol) at room temperature. The reaction mixture was degassed and stirred at 150° C. under N₂ overnight. LC/MS test showed that about 50% of the starting material was remaining and the desired adduct was one of the major peaks ([M+1]=525). Solid was filtered and solvent was removed. The residue was subjected to mass-triggered HPLC purification to give 32 mg of the adduct as brown oil. To a solution of the adduct (32 mg, 0.061 mmol) in 10 mL of DCM was added mCPBA (63 mg, 0.37 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 20 mins allowed to warm to room temperature. LC/MS test showed that starting material was all gone and the desired sulfoxide ([M+1]=557) was the major peak. The reaction mixture was quenched with NH₄Cl aqueous solution and diluted with ethyl acetate. The organic solution was separated, dried and concentrated. The residue was subjected to a mass-triggered HPLC purification to give 27 mg of the desired sulfoxide as clear oil. This was deprotected with TFA to give Example 721.

Example 730 N-(3-(2-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethylamino)propyl)-3-phenylpropanamide

Example 730 was prepared from Reference Compound 75 by the following way:

To a solution of Reference Compound 75 (10 mg, 0.02 mmol) in 2 mL of DMF were added N-(3-aminopropyl)-3-phenylpropanamide (9 mg, 0.04 mmol) and Et₃N (21 μL, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. HPLC/MS test showed that the starting material was gone and the desied product ([M+1]=601) was detected as a major peak. Reaction mixture was subjected to mass-triggered HPLC purification to give 8 mg of Example 730.

By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula Ia, Ib or Ic, as identified in Table 2, are obtained. Table 2 also documents the physical data obtained from the associated examples above.

TABLE 2 EC₅₀ EC₅₀ Physical Data 3D7 W2 Com- MS (M/z) strain strain pound Structure and/or ¹H NMR (μM) (μM) 1

392.5 (M + 1)    0.46 0.473 2

376 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ 7.93 (d, J = 7.6 Hz, 2H); 7.33 (t, J = 7.6 Hz, 2H); 7.19 (t, J = 7.6 Hz, 2H); 6.97 (d, J = 7.6 Hz, 2H); 6.81 (d, J = 7.6 Hz, 1H); 5.08 (m, 1H); 4.85-4.67 (m, 2H); 3.93-3.38 (m, 6H); 2.17-2.08 (ss, 6H)    3.48 3.348 3

412.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.70-7.76 (m, 2H); 7.22 (t, J = 8.8 Hz, 2H); 6.97(t, J = 8.8 Hz, 2H), 6.8-6.77 (m, 2H); 5.16 (s, 2H); 4.24 (m, 2H), 4.07 (m, 2H); 1.76 (s, 6H). Elemental Analysis: (compound + 2HCl + 0.50 H₂O): Elemental Analysis: % C, 53.56; H, 5.31; N, 14.19 (calculated). % C = 53.98/53.69; % N = 14.07-13.97; % H =    0.02 0.025 5.16/4.98 (experimental). 4

384.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.59-7.56 (m, 2H); 7.12 (t, J = 8.8 Hz, 2H); 6.86 (t, J = 8.8 Hz, 2H); 6.68-6.65 (m, 2H); 5.04-5.00 (m, 2H); 4.08-3.92 (m, 6H).    0.02 0.023 5

438.2 (M + 1)    4.33 >8.9 6

358.4 (M + 1)    4.38 4.643 7

340.4 (M + 1)   15.82 7.78 8

376.4 (M + 1)    0.62 0.501 9

434.4 (M + 1)   13.84 3.988 10

412.4(M + 1)    1.39 1.284 11

394.4 (M + 1)    0.2 0.168 12

448.4 (M + 1)    7.4 2.956 13

430.4 (M + 1)  0.26 0.137 14

464.5 (M + 1)    3.59 5.871 15

400.4 (M + 1)    2.63 2.111 16

395.4 (M + 1)   14.13 3.325 17

398.4 (M + 1)    0.09 0.064 18

412.2 (M + 1)   12.27 8.139 19

472.2 (M + 1)    0.07 0.059 20

474.2 (M + 1)    0.11 0.121 21

474.0 (M + 1)    0.1 0.078 22

412.2(M + 1)    1.3 0.691 23

408.2 (M + 1) >10.58 10.489 24

320.3 (M + 1)    8.92 2.862 25

426.2 (M + 1) >10.6 4.347 26

323.3 (M + 1) >10 5.521 27

400.2 (M + 1)    9.61 5.984 28

327.2 (M + 1) ¹H NMR (300 MHz, DMSO-d₆): δ 7.81-7.72 (m, 2H), 7.11 (m, 2H), 6.97 (m, 2H), 6.56-6.52 (m, 2H), 3.86 (s, 2H), 3.55 (m, 2H), 3.02 (m, 2H)    0.2 0.175 29

430.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.64-7.70 (m, 1H); 6.95- 6.91 (m, 3H); 6.33-6.39 (m, 1H); 6.27-6.22 (m, 1H); 4.97 (s, 2H); 4.17 (m, 2H); 3.73 (t, J = 2.8 Hz, 2H); 1.36 (s, 6H). Elemental Analysis: (compound + 2HCl + 0.40 H₂O): Elemental Analysis: % C, 51.85; % H, 4.91; % N, 13.74; (calculated). % C = 51.73, 51.85; % N = 13.5.13.51; % H = 4.87, 4.94 (experimental).    0.03 0.036 30

402.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.64- 7.59 (m, 2H); 6.96-6.89 (m, 2H); 6.38-6.34 (m, 1 H); 6.27-6.23 (m, 1H); 4.74-4.63 (m, 2H); 3.94- 3.41 (m, 6H).    0.03 0.023 31

397.2(M + 1)   13.08 6.893 32

398.2 (M + 1)    0.21 0.219 33

438.2(M + 1)    0.74 1.617 34

398.4 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.64-7.60 (m, 2H); 6.93- 6.87 (m, 2H); 6.80-6.75 (m, 2H); 6.49-6.45 (m, 2H); 4.71-4.70 (m, 2H); 3.85 (t, J = 5.2 Hz, 1H); 3.82 (t, J = 5.2 Hz, 1H) 3.72 (t, J = 5.2 Hz, 1H); 3.63 (t, J = 5.2 Hz, 1H); 2.83 (m, 2H); 2.54 (m, 2H).    0.07 0.075 35

412.2(M + 1)    0.12 0.105 36

384.4 (M + 1)    0.05 0.034 37

408.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.72 (m, 2H); 7.18 (t, J = 8.0 Hz, 2H); 7.02 (m, 2H), 6.7 (m, 2H); 5.19 (s, 2H); 4.07 (m, 2H), 2.21 (s, 6H); 1.77 (s, 6H)    0.05 0.043 38

380.4 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.74-7.71 (m, 2H); 7.21- 7.17 (m, 2H); 7.03 (t, J = 8.0 Hz, 2H); 6.67 (d, J = 8.4 Hz, 2H); 5.17-5.15 (m, 2H); 4.22-3.98 (m, 6H); 2.22 (s, 3H).    0.01 0.013 39

428.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.70 (m, 2H); 7.21(m, 4H); 6.8(m, 2H), 4.26 (m, 2H); 4.0 (m, 2H), 1.77 (s, 6H)    0.02 0.024 40

400.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59- 7.56 (m, 2H); 7.15-7.09 (m, 4H); 6.68-6.65 (m, 2H), 5.05 (m, 2H); 4.04- 3.87 (m, 6H).    0.01 0.009 41

454.2 (M + 1)    2.65 1.79 42

502.3 (M + 1)    6.1 4.611 43

488.2 (M + 1)    0.18 0.149 44

385.2(M + 1)    0.72 0.477 45

410.2(M + 1)    0.98 1.335 46

454.2(M + 1)   13.99 3.11 47

409.2(M + 1)    6.98 6.183 48

417.2(M + 1)    1.84 1.752 49

518.2(M + 1)    2.29 1.9 50

452.2(M + 1)    0.18 0.187 51

400.2(M + 1)    0.07 0.062 52

380.2(M + 1)    3.14 3.36 53

396.2(M + 1)    2.27 1.703 54

445.3(M + 1)    1.29 0.764 55

400.3(M + 1)    0.66 0.437 56

384.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.55-7.53 (m, 1H); 7.47- 7.45 (m, 2H); 7.15 (m, 1H); 6.96-6.94 (m, 2H); 6.84-6.81 (m, 2H); 5.20(m, 2H); 4.25-4.20 (m, 6H), 3.35 (s, NH).    0.01 0.013 57

474.2(M + 1)    0.31 0.294 58

456.2(M + 1)    0.47 0.28 59

456.2(M + 1)    1.09 0.735 60

470.2(M + 1)    2.46 2.129 61

520.2(M + 1)    9.24 62

488.2(M + 1)    4.74 4.738 63

520.2(M + 1)    1.95 1.606 64

468.2(M + 1)    9.37 6.465 65

448.2(M + 1)    0.47 0.509 66

430.2(M + 1)    0.22 0.244 67

402.2(M + 1)    0.19 0.197 68

424.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.71-7.67 (m, 2H); 7.22 (t, J = 8.8 Hz, 2H); 6.97- 6.95 (m, 2H), 6.8-6.77 (m, 2H); 5.15 (s, 2H); 4.19- 3.99 (m, 4H), 3.74-3.58 (m, 2H); 2.9-2.82 (m, 1H); 0.98-0.97 (m, 4H).    0.15 0.264 69

440.2 (M + 1)    0.08 0.094 70

412.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.50- 7.48 (m, 2H); 7.44-7.40 (m, 2H); 7.18 (m, 1H); 6.98 (t, J = 8.8 Hz, 2H); 6.82-6.79 (m, 2H); 5.18 (m, 2H); 4.25 (t, J = 4.8 Hz, 2H); 4.07 (t, J = 4.8 Hz, 2H); 1.76 (s, 6H)    0.05 0.079 71

418.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.7 (m, 2H); 7.28-7.22 (m, 2H); 6.71 (m, 1H); 6.64 (m, 1H); 5.16 (s, 2H); 4.18-4.01 (m, 6H)    0.0 0.004 72

462.2(M + 1)    0.95 0.589 73

434.2(M + 1)    0.08 0.059 74

484.2(M + 1)    0.07 0.067 75

394.2(M + 1)    0.25 0.19 76

504.2(M + 1)    0.06 0.061 77

414.2(M + 1)    0.06 0.039 78

418 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.72-7.68 (m, 2H); 7.23 (t, J = 8.8 Hz, 2H); 7.08 (t, J = 8.8 Hz, 1H); 6.91 (dd, J = 3.2 Hz, J = 5.8 Hz, 1H); 5.16 (m, 2H); 4.22-4.05 (m, 6H)    0.01 79

430.2(M + 1)    0.11 0.09 80

402.2(M + 1)    0.06 0.063 81

395.2(M + 1)    0.3 0.449 82

457.2(M + 1)    0.0 0.007 83

394.2(M + 1)    0.08 0.131 84

394.2(M + 1)    0.05 0.074 85

408.2(M + 1)    0.02 0.031 86

434.2(M + 1)    0.71 0.755 87

434.2(M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.71-7.68 (m, 2H); 7.21 (t, J = 8.8 Hz, 2H); 7.03 (d, J = 8.0 Hz, 2H) 6.67 (d, J = 8.4 Hz, 2H); 5.35- 4.96 (m, 2H); 4.37-3.88 (m, 4H); 3.49-3.31 (m, 3H); 3.25-3.13 (m, 2H); 2.23 (s, 3H); 2.11-1.8 (m, 4H)    0.02 0.012 88

422.6(M + 1)    0.15 0.081 89

406.2(M + 1)    0.05 0.073 90

420.2(M + 1)    0.65 0.6 91

420.2(M + 1)    0.12 0.154 92

434.2(M + 1)    1.3 1.484 93

434.2(M + 1)    1.67 1.512 94

446.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59- 7.56 (m, 2H); 7.2-7.11 (m, 3H); 6.6-6.57 (m, 2H); 5.04 (s, 2H); 4.14 (m, 2H); 3.97 (m, 2H); 1.69 (s, 6H).    0.04 0.052 95

420.2(M + 1)    1.54 0.707 96

420.2(M + 1)    0.58 0.321 97

456.2(M + 1)    0.04 0.021 98

456.2(M + 1)    0.01 0.008 99

407.2(M + 1)   0.81 0.658 100

423.2(M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.78-7.68 (m, 2H); 7.16 (t, J = 8.8 Hz, 2H); 7.02 (d, J = 8.0 Hz, 2H) 6.64- 6.60 (m, 2H); 5.17-5.07 (m, 2H); 4.13-3.86 (m, 4H); 2.7 (s, 2H); 2.22 (s, 3H); 1.32 (s, 6H).    0.15 0.143 101

493.6(M + 1)    5.09 4.373 102

547.6(M + 1)    0.65 0.426 103

395.2(M + 1)    1.02 104

423.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 MHz) δ7.76-7.73 (m, 2H); 7.02- 6.95 (m, 4 H); 6.49 (m, 2H), 4.96-4.80 (m, 2H); 4.25-4.08 (m, 1H); 3.83- 3.73 (m, 2H); 3.76-3.73 (m, 2H); 2.20 (s, 3H); 1.98 (m, 1H); 0.96 (t, J = 6.8 Hz, 6H).    0.01 0.007 105

435.2(M + 1)    0.85 106

471.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.64-7.59 (m, 2H); 7.13- 6.85 (m, 9 H); 6.83 (t, J = 8.4 Hz, 2H); 4.73-4.35 (m, 3H); 3.94-3.49 (m, 4H); 4.03-3.87 (m, 2H); 2.93-2.88 (m, 2H); 2.11 (s, 3H).    0.0 0.004 107

475.2(M + 1)    0.01 0.01 108

409.2(M + 1)    0.96 109

471.2(M + 1)    0.04 110

437.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.65- 7.62 (m, 2H); 6.92-6.84 (m, 4 H); 6.49 (m, 2H), 6.39 (t, J = 8.8 Hz, 2H). 4.95-4.62 (m, 2H); 4.18 (d, J = 8.4 Hz, 1H); 4.03- 3.87 (m, 2H); 3.74-3.64 (m, 2H); 2.1 (s, 3H); 0.9 (d, J = 7.2 Hz, 9H).    0.02 0.015 111

471.2(M + 1)    0.02 112

533.6(M + 1)    1.43 113

323.2(M + 1) ¹H NMR (400 MHz, CD₃OD) 7.73(d, J = 6.8 Hz, 2H), 7.00-6.99 (m, 4H), 6.49 (d, J = 8.0 Hz, 2H), 4.01 (s, 2H), 3.72(s, 2H), 3.15(s, 2H), 2.19(s, 3H).    0.15 0.146 114

409.2(M + 1)    1.34 1.35 115

477.2(M + 1)    0.15 0.153 116

435.2(M + 1)    1.64 1.509 117

449.2(M + 1)    1.26 1.186 118

485.6(M + 1)    0.15 0.135 119

513.4(M + 1)    4.74 120

477.2(M + 1)    0.11 0.123 121

463.4(M + 1)    0.02 0.033 122

487.2(M + 1)    0.18 0.154 123

493.2(M + 1)    0.03 124

525.2(M + 1)    0.04 0.028 125

471.3 (M + 1)    0.05 0.044 126

536.2(M + 1)    0.1 0.08 127

525.4 (M + 1)    0.06 0.051 128

539.2(M + 1)    1.18 0.743 129

473.2(M + 1)    0.01 0.006 130

473.2(M + 1)    0.01 131

492.0(M + 1)    0.04 0.03 132

554.2(M + 1)    0.1 0.082 133

492.0(M + 1)    0.05 0.039 134

437.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.76- 7.73 (m, 2H); 7.02-6.95 (m, 4 H); 6.50 (d, J = 7.2 Hz, 2H), 4.95-4.72 (m, 2H); 4.59-4.51 (m, 1H); 4.08-3.51 (m, 4H); 2.20 (s, 3H); 1.86 (m, 1H); 1.59(m, 1H); 1.48 (m, 1H); 0.96 (d, J = 7.2 Hz, 6H),    0.01 0.007 135

471.2(M + 1)    0.05 0.033 136

319.1 (M + 1) ¹H NMR (400 MHz, CD₃OD) 9.04 (s, 1H); 8.03(dd, J = 1.2 Hz, J = 4.8 Hz, 1H), 7.97 (m, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.41 (d, J = 8.4 Hz, 2H) 2.1(s, 3H).    2.02 2.693 137

457.2(M + 1)    0.01 0.012 138

457.2(M + 1)    0.01 0.015 139

420.2(M + 1)    0.16 0.165 140

434.2(M + 1)    0.09 0.128 141

448.2(M + 1)    0.07 0.09 142

462.4 (M + 1)    0.08 0.12 143

437.2(M + 1)    0.15 0.219 144

448.2(M + 1)    0.05 0.073 145

477.5 (M + 1)    0.09 0.068 146

470.5 (M + 1)    0.02 0.014 147

464.5 (M + 1)    2.43 1.519 148

478.5(M + 1)    4.06 1.432 149

484.5 (M + 1)    0.02 0.011 150

642.5(M + 1)    0.96 0.673 151

628.5 (M + 1)    0.82 0.386 152

685.4 (M + 1)    3.87 0.873 153

420.5(M + 1)    0.06 0.032 154

493.5 M + 1)    4.27 3.411 155

671.6 (M + 1)    2.14 0.491 156

451.5(M + 1)    1.83 0.458 157

485.5 (M + 1)    0.1 0.097 158

521.5 (M + 1)    7.54 4.763 159

925.1(M + 1)    5.7 2.91 160

527.5 (M + 1)    4.32 2.39 161

468.2(M + 1)    0.54 0.51 162

420.5 (M + 1)    1.78 1.376 163

410.1(M + 1)    0.02 0.026 164

506.2(M + 1)  >9.81 3.757 165

461.2(M + 1) >10.23 4.642 166

423.2(M + 1)    2.87 2.229 167

422.2(M + 1)    0.18 0.145 168

456.2(M + 1) 0.01 0.011 169

422.5 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59- 7.56 (m, 2H); 7.13-7.00 (m, 2H); 6.95-6.93 (m, 2 H); 6.56-6.54 (m, 2H); 5.17-4.8 (m, 2H); 4.37- 3.72 (m, 5H); 1.23-1.19 (m, 1H); 1.03 (d, J = 8.8 Hz, 3 H); 1.03 (d, J = 8.8 Hz, 3 H); 0.95 (d, J = 8.8 Hz, 3H).    0.04 170

436.2(M + 1)    0.09 0.054 171

563.2(M + 1)    0.17 0.214 172

538.4 (M + 1)    0.1 0.088 173

489.2 (M + 1)    0.14 0.133 174

503.5 (M + 1)    6.06 1.475 175

455.2(M + 1)    0.08 0.105 176

472.2(M + 1)    2.75 1.791 177

498.5 (M + 1)    0.43 0.43 178

491.5 (M + 1)    3.05 3.321 179

491.5 (M + 1)    4.79 1.072 180

498.5 (M + 1)    0.73 0.609 181

515.5 (M + 1)    2.68 1.811 182

484.5 (M + 1)    1.37 1.076 183

514.5 (M + 1)    1.9 1.342 184

490.5 (M + 1)    3.65 0.859 185

641.3(M + 1)    0.35 0.136 186

579.3 (M + 1)    5.63 2.56 187

541.3 (M + 1)    6.68 3.551 188

493.6(M + 1)    0.79 1.097 189

479.6(M + 1)    0.37 0.392 190

462.2(M + 1)    0.94 1.073 191

327.2(M + 1) ¹H NMR: (300 MHz, DMSO-d₆): δ 2.50-2.52 (2H, t, J = 1.5 Hz), 3.54-3.58 (2H, t, J = 2.1 Hz), 3.87 (s, 2H), 6.53- 6.58 (m, 2H), 6.91-7.02 (m, 3H), 7.27-7.36 (m, 1H), 7.50 (1H, d, J = 10.5 Hz), 7.62(1H, d, J = 7.8 Hz), 7.79 (s, 1H)    0.17 0.151 192

361.1(M + 1) ¹H NMR (400 MHz, CDCl₃) δ 7.75- 7.70 (m, 2H) 7.25-7.70 (m, 2H) 7.25-7.19 (m, H), 7.05-7.02 (m, 2H), 6.48- 6.41 (m, 2H), 4.16(s, 2H), 3.70 (m, 2H), 3.24 (m, 2H).    0.11 0.095 193

434.2(M + 1)    0.09 0.075 194

486.2(M + 1)    0.05 195

452.1(M + 1)    0.02 0.02 196

452.1(M + 1)    0.32 0.34 197

555.3 (M + 1)    4.16 1.04 198

409.2(M + 1)    1.36 199

421.2(M + 1)    0.24 0.157 200

421.2(M + 1)    0.91 201

485.6(M + 1)    0.24 0.131 202

471.2(M + 1)    0.16 0.102 203

505.1 (M + 1)    0.97 0.369 204

423.2(M + 1)    0.01 0.01 205

423.2 (M + 1)    0.0 0.004 206

443.2 (M + 1)    1.2 1.17 207

357.1 (M + 1)    9.31 2.421 208

513.2 (M + 1)    5.87 1.057 209

435.2 (M + 1)   11.62 4.362 210

515.2 (M + 1)    0.04 0.026 211

435.2 (M + 1)    0.3 0.283 212

421.2(M + 1)    1.95 1.984 213

499.1 (M + 1)    3.8 4.823 214

476.3 (M + 1)    2.85 2.008 215

435.2 (M + 1)    0.83 0.65 216

449.2 (M + 1)    0.3 0.248 217

361.1(M + 1) ¹H NMR (300 MHz, DMSO-d₆) δ 3.04 (2H, t, J = 5.1 Hz), 3.57 (s, 2H), 3.88 (s, 2H), 6.42-6.52 (m, 2H), 6.94- 7.00 (m, 1H), 7.28-7.38 (m, 2H), 7.48 (1H, d, J = 7.2 Hz), 7.58 (1H, d, J = 7.8 Hz), 8.27 (s, 1H)    0.13 0.106 218

569.0 (M + 1)    4.71 4.015 219

555.9 (M + 1)    4.97 3.414 220

448.2(M + 1)    1.13 0.937 221

486.0 (M + 1)    0.09 0.083 222

493.0 (M + 1)    0.14 0.103 223

493.0 (M + 1)    0.26 0.206 224

469.1 (M + 1)    0.02 0.018 225

469.1 (M + 1)    0.55 0.316 226

509.1 (M + 1)    0.48 0.348 227

442.2 (M + 1)    0.09 0.103 228

417.9 (M + 1)    0.01 0.008 229

446.2 (M + 1)    0.01 0.007 230

510.2 (M + 1)    0.32 0.255 231

483.3 (M + 1)    0.09 0.07 232

455.2 (M + 1)    0.05 0.044 233

459.2 (M + 1)    0.01 0.015 234

461.0 (M + 1)    0.13 0.111 235

427.2 (M + 1)    0.54 0.496 236

666.2 (M + 1)    5.25 2.063 237

632.3 (M + 1)    7.19 5.722 238

653.2 (M + 1)    3.56 1.305 239

619.3 (M + 1)    1.84 0.629 240

576.2 (M + 1)   10.49 6.99 241

542.2 (M + 1)    5.27 2.36 242

624.1 (M + 1)    2.09 0.288 243

589.3 (M + 1)    2.97 0.697 244

423.2 (M + 1)    2.4 1.329 245

439.2 (M + 1)    2.53 1.804 246

585.3 (M + 1)    3.88 1.791 247

618.1 (M + 1)    1.42 3.937 248

583.3 (M + 1)    7.01 4.559 249

334.3 (M + 1)    5.39 5.055 250

611.7 (M + 1)    3.88 3.979 251

463.3 (M + 1)    3.68 2.548 252

707.3 (M + 1)    3.03 0.631 253

679.2(M + 1)    0.78 0.254 254

673.4 (M + 1)    3.44 0.727 255

517.3 (M + 1)    0.61 0.653 256

483.2 (M + 1)    1.16 1.475 257

511.3 (M + 1)    6.68 7.003 258

608.1 (M + 1)    4.92 3.513 259

579.2 (M + 1)    5.32 3.022 260

573.3 (M + 1)    7.64 5.009 261

545.1 (M + 1)    7.06 4.126 262

343.1(M + 1) ¹H NMR (DMSO, ppm): δ 7.94(s, 1H), 7.80-7.74(m, 2H), 7.18-7.09(m, 4H), 6.56 (d, J = 8.7 Hz, 2H), 3.87(s, 2H), 3.55(s, 2H), 3.02(t, J = 5.4 Hz, 2H).    0.24 0.267 263

419.2 (M + 1)    0.35 0.653 264

391.2 (M + 1)    0.11 0.154 265

434.2 (M + 1)    1.35 1.585 266

319.2 (M + 1) ¹H NMR: (300 MHz, CDCl₃) δ 7.70 (s, 1H), 7.56 (1H, d, J = 7.8 Hz), 7.21-7.15 (1H, t, J = 7.5 Hz), 7.04 (3H, d, J = 8.1 Hz), 5.21 (1H, s), 4.18 (s, 2H), 3.73- 3.68 (t, 2H, J = 5.4 Hz), 3.23-3.18 (t, 2H, J = 5.4 Hz), 2.34 (s, 3H), 2.29 (s, 3H)    1.17 1.313 267

655.4 (M + 1)    0.99 0.474 268

513.2 (M + 1)    0.01 0.012 269

527.2 (M + 1)    0.01 0.006 270

541.2 (M + 1)    0.05 271

479.0 (M + 1)    0.44 0.385 272

555.7 (M + 1)    3.59 3.26 273

531.7(M + 1)    3.33 3.471 274

517.7(M + 1)    5.14 5.673 275

529.3 (M + 1)    3.83 3.95 276

506.1 (M + 1) 277

465.1 (M + 1) 278

341.2 (M + 1) ¹H NMR (400 MHz, CDCl₃) δ 7.70- 7.53 (m, 2H), 7.12-7.04 (m, 3H), 6.58 (d, J = 8.4 Hz, 2H), 5.12 (s, 1H), 4.18 (s, 2H), 3.73 (m, 2H), 3.23 (m, 2H), 2.98 (s, 1H), 2.29 (s, 3H).    0.21 0.269 279

339.1 (M + 1) ¹H NMR (300 MHz, CDCl₃) δ□ 7.00-7.62 (m, 1H), 7.24- 7.15 (m, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.59 (d, J = 8.1 Hz, 2H), 5.15 (s, 1H), 4.18 (s, 2H), 3.72 (m, 2H), 3.22 (m, 2H), 2.29(s, 3H)    3.52 3.828 280

341.2 (M + 1) ¹H NMR (300 MHz, CDCl₃) δ□7.70-7.62(m, 1H), 7.01 (d , J = 8.1 Hz, 2H), 6.92- 6.76 (m, 2H), 6.52 (d, J = 8.1 Hz, 2H), 5.33 (s, 1H), 4.23(s, 2H), 3.77(m, 2H), 3.26 (m, 2H), 2.25(s, 3H).    4.71 4.652 281

566.3 (M + 1)    0.82 0.596 282

566.3 (M + 1)    0.12 0.117 283

527.3 (M + 1)    5.52 3.494 284

410.2 (M + 1)    0.05 0.037 285

424.2 (M + 1)    0.18 0.177 286

486.1 (M + 1)    1.38 1.502 287

438.2(M + 1)    4.36 7.262 288

472.2 (M + 1)    0.89 1.388 289

436.1 (M + 1)    3.88 0.747 290

512.2 (M + 1)    0.44 0.397 291

526.2 (M + 1)    1.2 0.567 292

375.1 (M + 1) ¹H NMR: (300 MHz, CDCl₃): δ 7.66- 7.60 (m, 2H), 7.29-7.21 (m, 1H), 7.01-6.99 (m, 2H), 6.55-6.50 (m, 1H), 6.43-6.40 (m, 1H), 4.28(s, 2H), 3.75-3.64 (m, 2H), 3.32-3.25 (m, 5H)    0.15 0.156 293

432.0 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.47- 7.43 (m, 2H); 7.27-7.22 (m, 1 H); 7.14-7.07 (m, 2H); 6.7 (m, 1H); 6.53 (m, 1H); 4.99-4.80 (m, 2H); 4.04 (m, 2H); 3.85 (m, 4 H).    0.02 294

460.2(M + 1)    0.11 0.113 295

512.4 (M + 1)    0.21 0.283 296

526.7 (M + 1)    0.28 0.424 297

289.2(M + 1) ¹H NMR: (300 MHz, CDCl₃): □ □7.72-7.75 (m, 2H), 7.03-7.10 (m, 2H), 4.16 (s, 2H), 3.86 (t, J = 5.4 Hz, 2H), 3.23 (t, J = 5.4 Hz, 2H), 1.04 (s, 9H).    5.29 8.505 298

930.5 (M + 1)    0.61 0.193 299

337.2(M + 1)  >8.74 9.398 300

337.2 (M + 1)    1.11 1.169 301

462.2 (M + 1)    0.03 0.047 302

480.2 (M + 1)    0.17 0.149 303

518.3 (M + 1)    0.54 0.439 304

516.2(M + 1)    3.21 2.946 305

494.2 (M + 1)    0.09 0.094 306

519.2(M + 1)    0.42 0.334 307

422.2(M + 1)    0.03 0.022 308

450.3 (M + 1)    0.06 0.068 309

438.2(M + 1)    0.08 0.068 310

452.2(M + 1)    0.52 0.397 311

509.0(M + 1)    0.09 0.072 312

553.0(M + 1)    1.64 0.897 313

460.2(M + 1)    0.02 0.004 314

432.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59-7.55 (m, 2H); 7.22-7.12 (m, 3 H); 6.60- 6.51 (m, 2H); 5.13-4.89 (m, 2H); 4.49 (m, 2H); 4.02-3.90 (m, 3H); 1.43 (d, J = 6.8 Hz, 3H).    0.03 0.02 315

515.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ 8.94- 8.90 (m, 2H); 7.59-7.44 (m, 2 H); 7.21-7.13 (m, 3H); 6.59-6.51 (m, 2H); 5.24- 5.09 (m, 2H); 4.04-3.85 (m, 5H); 3.38-3.28 (m, 2H).    0.02 0.008 316

526.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59- 7.52 (m, 2H); 7.27-7.22 (m, 2 H); 7.03-6.92 (m, 2H); 6.53-6.44 (m, 2H); 5.17 (m, 1H); 4.23 (m, 1H); 3.92- 3.72 (m, 3H); 3.51-3.42 (m, 2H); 3.22 (m, 1H); 3.09- 3.06 (m, 1H).    0.02 0.014 317

474 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59- 7.56 (m, 2H); 7.22-7.11 (m, 3 H); 6.58-6.49 (m, 2H); 5.2-4.88 (m, 2H); 4.5-3.62 (m, 5H); 1.91-1.88 (m, 1H); 1.5-1.46 (m, 1H); 1.27-0.87 (m, 7H).    0.02 318

460.2(M + 1)    0.15 0.098 319

544.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.58- 7.53 (m, 2H); 7.22-7.12 (m, 6 H); 6.59-6.49 (m, 2H); 5.3-5.25 (m, 1H); 4.93-4.73 (m, 2H); 4.05-3.65 (m, 4H); 3.15--3.1 (m, 1H); 3.07- 2.97 (m, 1H).    0.04 0.027 320

460.2 (M + 1)    0.17 0.103 321

444.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.58- 7.55 (m, 2H); 7.22-7.14 (m, 3 H); 6.61-6.51 (m, 2H); 5034-5.20 (m, 2H); 4.53- 4.39 (m, 2H); 4.15-4.1 (m, 2H); 4.02-3.95 (m, 3H); 1.18 (m, 1H); 1.06 (d, J = 7.2 Hz, 2H); 0.963 (d, J = 7.2 Hz, 2H).    0.02 0.011 322

474.2 (M + 1)    0.04 323

474.2 (M + 1)    1.73 1.329 324

508.2(M + 1)    0.03 0.03 325

486.2 (M + 1)    0.03 0.029 326

474.2(M + 1)    0.03 0.022 327

432.2(M + 1)    0.03 0.021 328

533.2(M + 1)    0.34 0.229 329

337.2 (M + 1)    0.15 0.116 330

341.2 (M + 1) ¹H NMR: (300 Hz, DMSO-d₆) δ7.47(s, 1H), 7.32(1H, d, J = 4.5 Hz), 7.17(1H, d, J = 3.6 Hz), 7.05(s, 1H), 3.91(2H, d, J = 7.5 Hz), 6.44(2H, d, J = 7.8 Hz), 3.87(s, 2H), 3.55(s, 2H), 3.02(s, 2H), 2.15(s, 3H)    4.47 331

345.1 (M + 1) ¹H NMR (300 MHz, CDCl₃) δ7.76- 7.72 (m, 2H) 7.08-6.99 (m, 3H) 6.50-6.43 (m, H) 6.38- 6.35 (m, 1H) 5.26 (s, H) 4.17 (s, 2H) 3.73-3.69 (m, 2H) 3.27-3.23 (m, 2H) 2.05 (s, 2H).    0.14 332

570.3 (M + 1)    1.04 333

563.2(M + 1)    1.11 334

509.2(M + 1)    0.05 335

565.2(M + 1)    2.3 336

495.2(M + 1)    0.04 337

486.2(M + 1) >10 338

458.2(M + 1)    0.19 339

500.2 (M + 1)    0.52 340

458.2 (M + 1)    0.2 341

522.3 (M + 1)    0.01 342

506.2 (M + 1)    5.24 343

506.2 (M + 1)    7.5 344

601.2 (M + 1)    0.21 345

587.2 (M + 1) 346

858.1(M + 1)  >8.8 347

520.3 (M + 1)    5.92 348

499.9 (M + 1)    0.05 349

481.6 (M + 1)    7.48 350

409.2 (M + 1)    0.66 351

439.2 (M + 1)    1.24 352

394.2 (M + 1)    0.01 353

437.2(M + 1)    0.21 354

306.2(M + 1) H-NMR (300 MHz, CDCl₃): 2.29(s, 3H), 3.03(m, 2H), 3.43(s, 1H), 3.81(m, 2H), 3.90(s, 2H), 5.57(s, 1H), 6.60-6.63 (2H, d, J = 8.4 Hz), 7.06- 7.09(2H, d, J = 8.1 Hz), 7.79(m, 2H), 8.44-8.46(m, 2H)    6.32 0.564 355

600 (M + 1)    2.81 2.266 356

459.2(M + 1)    1.26 0.872 357

532.3 (M + 1)    7.49 4.712 358

475.2(M + 1)    0.13 0.049 359

511.2 (M + 1)    0.14 0.108 360

461.2(M + 1)    0.03 0.015 361

490.3 (M + 1)    2.35 1.141 362

470.6 (M + 1)    0.81 0.203 363

532.2 (M + 1)    1.75 1.133 364

514.6 (M + 1)    4.95 3.742 365

562.1(M + 1)    0.61 0.26 366

462.2 (M + 1)    3.47 1.824 367

474.2 (M + 1)    0.19 0.148 368

562.2 (M + 1)    0.52 0.286 369

529.2 (M + 1)    0.11 0.084 370

516.1 (M + 1)    4.35 8.345 371

546.6 (M + 1)    1.52 1.283 372

488.2 (M + 1)    0.69 0.554 373

474.3 (M + 1)    0.43 0.32 374

484.3 (M + 1)    0.59 0.248 375

480.2 (M + 1)    1.13 0.679 376

436.2 (M + 1)    0.06 0.079 377

450.3 (M + 1) 0.574 378

450.3 (M + 1)    0.06 0.063 379

426.2(M + 1)    0.06 0.05 380

498.3 (M + 1)    1.13 1.789 381

392.2 (M + 1)    1.97 1.798 382

363.2 (M + 1)    1.05 1.039 383

396.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.62-7.59 (m, 2H); 7.14- 7.04 (m, 2H); 6.85 (d, J = 2.4 Hz, 1H); 6.65-6.5 (dd, J = 2.7 Hz, J = 8.4 Hz, 1H); 4.0-3.98 (m, 4H); 2.16 (s, 3H); 2.00 (s, 6H); 1.64 (s, 6H).    0.05 0.032 384

484.3 (M + 1)    0.47 0.889 385

398.2 (M + 1)    0.02 0.02 386

498.3 (M + 1)    2.62 3.028 387

398.2 (M + 1)    0.11 0.08 388

498.3 (M + 1)    3.22 1.772 389

450.3 (M + 1)    0.06 0.051 390

473.3 (M + 1)    0.03 0.028 391

441.2 (M + 1)    0.01 0.007 392

436.3 (M + 1)    0.03 0.039 393

446.2 (M + 1)    0.02 394

474.0 (M + 1)    0.05 0.043 395

426.2 (M + 1)    0.44 0.246 396

440.2 (M + 1)    0.03 0.022 397

424.2 (M + 1)    2.45 1.673 398

391.2 (M + 1)    2.73 2.685 399

436.2 (M + 1)    0.22 0.196 400

518.2 (M + 1)    0.18 0.105 401

434.2 (M + 1)    0.02 0.012 402

484.3 (M + 1)    0.12 0.122 403

484.3 (M + 1)    0.51 0.543 404

420.2 (M + 1)    0.02 0.012 405

524.2 (M + 1)    0.02 0.012 406

412.2 (M + 1)    0.06 0.04 407

484.3 (M + 1)    0.71 0.523 408

426.2(M + 1)    0.93 0.908 409

408.1 (M + 1) ¹H-NMR: (MeOH-d4, 400 Hz) δ7.79- 7.69 (m, 2H), 7.21 (t, J = 8.4 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.2 Hz, 2H), 4.11 (s, 2H), 3.88 (m, 4H), 2.22 (s, 3H), 2.12 (s, 6H).    0.01 0.006 410

463.3 (M + 1)    0.06 0.037 411

378.2 (M + 1)    0.14 0.106 412

412.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.61- 7.57 (m, 2H), 6.94 (2H, J = 8.8 Hz, t), 6.81 (2H, J = 8.8 Hz, t), 6.47 (m, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.42 (m, 2H), 1.85 (s, 6H). Elemental Analysis: (compounds + 0.65 H₂O): C, 62.44; N, 16.55; H, 5.79, (calculated). C = 62.54/ 62.44; N = 16.35/16.29; H = 5.52/5.61 (experimental)    0.01 0.006 413

389.1 (M + 1) ¹H NMR: (300 Hz, DMSO-d₆) δ7.59(m, 2H), 7.35(t, J = 6.6 Hz, 1H), 7.12(t, J = 6.6, 2H), 6.68(d, J = 8.7 Hz, 1H), 6.42(d, J = 6.9 Hz, 1H), 3.88(d, J = 1.5 Hz, 2H), 3.68-3.61 (m, 2H), 3.57- 3.50(m, 2H), 3.02(t, J = 4.2 Hz, 2H), 1.04(t, J = 5.4 Hz, 3H)    0.18 0.131 414

436.2 (M + 1)    0.16 0.156 415

351.2 (M + 1)    0.01 0.013 416

371.2 (M + 1) ¹H-NMR (MeOH-d₄, 400 Hz) δ7.77- 7.73 (m, 2H); 7.25-7.18 (m, 4H); 6.84-6.82 (m, 2H); 4.38 (m, 2H); 3.95 (m, 2H); 2.11 (s, 6H).    0.01 0.016 417

428.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.75- 7.71 (m, 2H), 7.13-7.1 (m, 2H), 6.59 (t J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 3.80 (m, 2H), 3.65 (m, 2H), 3.31 (m, 2H), 1.95 (s, 6H). Elemental Analysis: (compound + 0.33 H₂O): Elemental Analysis: C, 60.11; N, 15.93; H, 5.57; (calculated). % C, 60.93/ 60.79; % N, 15.99/16.08; % H, 5.54/5.40 (experimental)    0.01 0.006 418

398.2 (M + 1)    0.09 0.146 419

446.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.59- 7.55 (m, 2H); 7.20-7.13 (m, 3H); 6.60 (dd, J = 10.8 Hz, J = 11.2 Hz, 1H); 6.53 (dd, J = 0.8 Hz, J = 2.4 Hz, 1H); 4.0 (m, 4H); 3.78 (m, 2H); 2.00 (s, 6H).    0.03 0.024 420

389.8 (M + 1)    0.02 0.028 421

430.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.73- 7.69 (m, 2H); 7.07-6.99 (m, 3H); 6.46-6.40 (m, 1H); 6.34-6.32 (m, 1H); 3.78 (m, 2H), 3.62 (m, 2H), 3.5 (m, 2H); 1.98 (s, 6H); 1.48 (s, 6H).    0.003 0.005 422

373.2 (M + 1)    0.01 0.021 423

446.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.70- 7.66 (m, 2H); 7.18-7.14 (m, 3H); 7.07 (t, J = 9.2 Hz, 1H); 6.8-6.78 (m, 1H); 6.64-6.60 (M, 1H); 2.04 (s, 6H).    0.01 0.009 424

389.1 (M + 1)    0.02 0.03 425

419.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.68- 7.65(m, 2H); 7.54 (d, J = 8.8 Hz, 2H); 7.17 (t, J = 8.8 Hz, 2H); 6.83 (d, J = 8.4 Hz, 2H); 4.07 (s, 2H); 4.03 (s, 2H); 3.82 (m, 2H); 2.06 (s, 6H).    0.01 0.012 426

362.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) 7.69 (m, 2H); 7.51 (d, J = 8.4 Hz, 2H); .7.07 (t, J = 8.8 Hz, 2H); 6.73 (d, J = 8.8 Hz, 2H); 4.01 (m, 2H); 3.78 (m, 2H); 1.86 (s, 6H).    0.18 0.271 427

460.2 (M + 1)    0.21 0.436 428

440.2 (M + 1)    0.17 0.242 429

470.2(M + 1)    0.02 0.036 430

445.2(M + 1)    0.01 0.019 431

499.2(M + 1)    0.07 0.08 432

506.2(M + 1)    0.06 0.067 433

528.2(M + 1)    0.04 0.049 434

444.2(M + 1)    0.02 0.019 435

416.2(M + 1)    0.05 0.098 436

496.3 (M + 1)    0.03 0.052 437

442.2(M + 1)    0.02 0.028 438

456.3 (M + 1)    0.02 0.023 439

458.3 (M + 1)    0.03 0.04 440

445.2(M + 1)    0.02 0.028 441

428.2(M + 1)    0.06 0.081 442

458.2(M + 1)    0.02 0.033 443

510.2(M + 1)    0.05 0.055 444

403.2 (M + 1) ¹H NMR: (300 MHz, CDCl₃) δ7.60- 7.55(m, 2H), 7.28-7.21(m, 1H), 7.03-6.97(m, 2H), 6.58- 6.53(m, 1H), 6.44-6.39(m, 1H), 4.29(s, 2H), 4.19- 4.10(m, 1H), 3.79(br, 1H), 3.55(br, 1H), 3.30-3.26(br, 2H), 1.18-1.16(br, 3H), 1.01-0.99 (br, 3H).    7.22 5.965 445

369.2 (M + 1)    2.6 3.272 446

355.2 (M + 1) H-NMR: (DMSO, 300 Hz): □δ 7.67- 7.63(m, 2H), 7.23-7.16(m, 1H), 7.03-6.97(m, 2H), 6.57- 6.41(m, 3H), 4.22(s, 1H), 3.69-3.55(m, 4H), 3.24(t, J = 4.8 Hz, 2H), 2.61(s, 2H), 1.17(t, J = 7.2 Hz, 3H)    0.31 0.243 447

361.0 (M + 1) ¹H NMR: (300 MHz, CDCl₃) δ7.76- 7.71 (m, 2H), 7.25-7.19 (m, 1H), 7.05-6.99 (m, 2H), 6.48- 6.41 (m, 2H), 5.44 (s, H), 4.17 (s, 2H), 3.73-3.70 (m, 2H), 3.27-3.23 (m, 2H)    0.23 448

414.2 (M + 1)    0.02 0.022 449

442.2(M + 1)    0.03 0.026 450

440.2(M + 1)    0.02 0.015 451

454.2(M + 1)    0.03 0.019 452

469.0(M + 1)    0.02 0.019 453

456.2(M + 1)    0.02 0.021 454

456.2 (M + 1)    0.02 0.008 455

443.0 (M + 1)    0.01 0.008 456

443.0 (M + 1)    0.02 0.015 457

494.2 (M + 1)    0.02 0.011 458

508.2 (M + 1)    0.02 0.017 459

504.2(M + 1)    0.04 0.024 460

526.2 (M + 1)    0.04 0.033 461

497.2 (M + 1)    0.03 0.022 462

426.2(M + 1)    0.05 0.037 463

456.2 (M + 1)    0.04 0.024 464

426.2(M + 1)    0.03 0.024 465

424.2 (M + 1)    0.0019 0.002 466

438.2 (M + 1)    0.03 467

452.2 (M + 1)    0.02 0.016 468

440.2 (M + 1)    0.03 0.02 469

440.2(M + 1)    0.02 0.016 470

427.1 (M + 1)    0.01 0.012 471

427.1 (M + 1)    0.03 0.03 472

478.2(M + 1)    0.05 0.037 473

492.2(M + 1)    0.03 0.021 474

488.2(M + 1)    0.13 0.088 475

510.0(M + 1)    0.04 0.03 476

480.9 (M + 1)    0.04 0.027 477

410.0 (M + 1)    0.07 0.055 478

440.0 (M + 1)    0.06 0.039 479

448.2(M + 1)    0.02 0.012 480

436.2(M + 1)    0.03 0.022 481

436.2(M + 1)    0.02 0.014 482

474.2(M + 1)    0.02 0.009 483

488.2(M + 1)    0.05 0.025 484

484.3 (M + 1)    0.04 0.023 485

506.2(M + 1)    0.03 0.023 486

477.0 (M + 1)    0.03 0.016 487

458(M + 1)    0.04 0.031 488

472.2(M + 1)    0.02 0.013 489

461.2(M + 1)    0.01 0.009 490

512.2(M + 1)    0.05 0.033 491

458 (M + 1)    0.08 0.055 492

446.2(M + 1)    0.05 493

355.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.62- 7.58 (m, 2H); 7.12-7.08 (m, 2H); 6.68-6.63 (m, 2H); 6.67 (m, 2H); 4.16 (m, 2H); 3.78 (m, 2H); 1.92 (s, 6H).    0.004 0.005 494

337.2(M + 1)    2.82 2.141 495

426.0(M + 1)    0.09 0.039 496

442.2(M + 1)    0.03 0.008 497

357.1(M + 1)    8.0 5.825 498

357.1(M + 1)    6.34 6.738 499

408.2(M + 1)    0.01 0.006 500

419.0 (M + 1)    1.56 1.1 501

369.2 (M + 1)    0.4 0.305 502

502.3 (M + 1)    1.39 1.373 503

450.3 (M + 1)    0.12 0.095 504

424.0(M + 1)    0.09 0.093 505

424.2(M + 1)    0.14 0.116 506

420.3(M + 1)    0.19 0.198 507

365.2(M + 1)    0.14 0.136 508

385.0 (M + 1)    0.13 0.126 509

387.2(M + 1)    0.13 0.134 510

387.2(M + 1)    2.05 1.564 511

403.1(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.74- 7.70 (m, 2H); 7.21 (t, J = 8.4 Hz, 1H), 7.08 (m, 2H); 6.49- 6.40 (m, 2H); 4.43 (s, 2H); 1.72 (s, 6H).    0.04 0.065 512

369.2(M + 1)    0.19 0.165 513

403.0 (M + 1)    0.17 0.195 514

355.1(M + 1)    0.03 0.024 515

405.1 (M + 1)    0.04 0.034 516

451.2 (M + 1)    0.03 0.026 517

394.1 (M + 1)    0.05 0.051 518

422.2 (M + 1)    4.98 2.888 519

414.2 (M + 1)    0.84 0.59 520

414.2(M + 1)    0.16 0.158 521

442.2 (M + 1)    5.0 3.026 522

437.0(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.61- 7.57 (m, 2H); 7.15-7.07 (m, 4H); 7.02-7.01(m, 1H); 4.0(m, 4H); 3.81 (m, 2H); 2.01 (s, 6H).    0.0017 0.002 523

399.0 (M + 1)   13.11 11.649 524

380.2 (M + 1)    0.04 0.057 525

433.5 (M + 1)    0.01 0.013 526

395.0 (M + 1)    1.12 0.974 527

376.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.61- 7.57 (m, 2H); 7.15-7.07 (m, 4H); 7.02-7.01(m, 1H); 4.0(m, 4H); 3.81 (m, 2H); 2.01 (s, 6H).    0.004 0.006 528

501.2(M + 1)    0.15 0.121 529

436.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.78- 7.75 (m, 2H); 7.06-6.97 (m, 4H); 6.56 (d, J = 8.4 Hz, 2H), 5.16 (s, NH); 4.33 (t, J = 4.8 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 4.16 (m, 2H); 2.29 (s, 3H); 1.95 (s, 6H); 1.45 (s, 6H).    0.002 0.004 530

482.2(M + 1)    1.23 6.422 531

400.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.67- 7.63 (m, 2H); 7.21-7.17 (t, J = 8.8 Hz, 2H), 4.15 (m, 2H); 3.79 (m, 2H); 2.72 (m, 1H); 1.95 (s, 6H); 1.72 (m, 2H); 1.58 (m, 2H); 1.46 (m, 1H); 1.1-1.05 (m, 5H).    0.04 0.057 532

442.2(M + 1)    0.02 0.009 533

426.2(M + 1)    0.03 0.022 534

453.2(M + 1)    0.04 0.019 535

390.2(M + 1)    2.72 2.351 536

397.2(M + 1)    6.4 5.93 537

394.2(M + 1)   11.91 8.342 538

407.2(M + 1)    7.67 8.065 539

393.2(M + 1)    3.06 3.123 540

375.2(M + 1) ¹H-NMR: (300 Hz, CD₃OD) δ7.74- 7.69(m, 2H), 7.42(s, 1H), 7.13-7.07(m, 2H), 4.84(s, 2H), 4.19-3.97(6H, m), 1.47(9H, s)    8.42 9.807 541

369.2(M + 1)    0.01 0.01 542

369.2(M + 1)    0.002 0.003 543

405.2(M + 1)    0.17 0.305 544

383.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.65- 7.62 (m, 2H); 6.95-6.91 (m, 1H); 6.72 (t, J = 9.2 Hz, 1H), 6.28-6.25 (m, 1H); 4.30 (s, 2H) 2.04 (s, 3H); 1.81 (s, 6H).    0.02 0.037 545

382.2(M + 1)    3.38 5.618 546

399.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.60- 7.56 (m, 2H); 7.09-7.05 (m, 2H); 6.99 (d, J = 8.0 Hz, 1H), 6.67(d, J = 2.4 Hz, 2H); 6.46(dd, J = 2.4 Hz, J = 8.0 Hz, 1H); 4.44 (s, 2H) 2.13 (s, 3H); 1.71 (s, 6H).    0.03 0.052 547

366.2(M + 1)    1.82 4.662 548

410.0 (M + 1)    2.63 5.549 549

399.1 (M + 1)    1.7 3.261 550

417.1 (M + 1)    2.56 3.6 551

421.0 (M + 1)    0.04 0.098 552

487.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.72- 7.67 (m, 4H); 7.2 (t, J = 8.8 Hz, 2H); 6.8 (d, J = 8.4 Hz, 2H), 4.01 (m, 4H), 3.86 (t, J = 4.4 Hz, 2H); 2.88 (s, 3H); 2.1 (s, 6H).    2.52 4.482 553

451.2(M + 1)    2.37 4.658 554

448.0 (M + 1)    0.0 0.007 555

391.2(M + 1)    0.01 0.016 556

385.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.72- 7.69 (m, 2H); 7.19-7.15 (4H, m); 6.67 (2H, J = 9.2 Hz, d); 4.64 (s, 2H); 4.64 (s, 2H); 3.99 (s, 2H), 2.91 (s, 2H), 1.43 (s, 6H).    0.06 0.075 557

428.2 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.74 (m, 2H); 7.19-7.15 (m, 2H); 6.69 (d, J = 8.8 Hz, 2H); 4.88 (s, 2H); 4.08 (s, 2H); 3.99 (s, 2H), 2.91 (s, 2H), 1.54 (s, 6H).    0.02 0.02 558

371.1 (M + 1) ¹H-NMR: (CDCl₃, 400 Hz) δ7.75-7.71 (m, 2H); 7.18 (d, J = 9.2 Hz, 2H); 6.99 (t, J = 8.8 Hz, 2H); 6.56 (d, J = 8.8 Hz, 2H); 5.37 (s, NH); 4.15 (s, 2H); 3.49 (s, NH); 3.42 (s, 2H); 1.22 (s, 6H).    0.06 0.089 559

389.0 (M + 1)    0.53 0.642 560

369.2(M + 1)    3.61 5.219 561

386.2(M + 1)    7.17 4.403 562

417.2(M + 1)    4.82 6.293 563

371.0 (M + 1)    0.31 0.445 564

389.0 (M + 1)    0.25 0.359 565

371.0 (M + 1)    0.07 0.105 566

402.2(M + 1)    5.48 4.463 567

429.2(M + 1)    6.46 8.458 568

449.0 (M + 1)  >8.04 >11.3 569

463.3 (M + 1)    9.27 7.916 570

472.2(M + 1)    5.68 5.562 571

492.1 (M + 1)    6.2 7.48 572

435.1 (M + 1)   11.18 8.73 573

408.2(M + 1)    0.04 0.055 574

412.1(M + 1)    0.08 0.111 575

430.2(M + 1)    0.08 0.081 576

446.2(M + 1)    0.2 0.234 577

437.1(M + 1)    0.63 0.611 578

351.2(M + 1)    0.25 0.339 579

355.2(M + 1)    0.18 0.146 580

373.2(M + 1)    0.15 0.169 581

380.2(M + 1)    0.65 0.668 582

471.1 (M + 1)    5.56 5.919 583

440.1 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.66 (dd, J = 5.2 Hz, J = 9.2 Hz, 2H); 7.11(t, J = 8.8 Hz, 2H); 6.81(t, J = 8.8 Hz, 2H); 6.72- 6.68(m, 2H); 4.04-3.99 (m, 4H); 2.01 (s, 6H); 1.66 (s, 6H).    0.01 0.009 584

456.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.60- 7.59 (m, 2H); 7.16-7.09 (m, 4H); 6.7(d, J = 8.4 Hz, 2H); 4.01(m, 4H); 2.01 (s, 6H); 1.65 (s, 6H).    0.02 0.021 585

458.1(M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.63- 7.60 (m, 2H); 7.14(t, J = 8.4 Hz, 2H); 7.01 (dd, J = 8.8 Hz, J = 18.8 Hz, 1H); 6.68- 6.63 (m, 1H); 6.5 (m, 1H); 4.03 (m, 2H); 4.01 (m, 2H); 2.01 (s, 6H); 1.66 (s, 6H).    0.01 0.007 586

474.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.63- 7.59 (m, 2H); 7.13 (t, J = 8.8 Hz, 2H); 6.97 (t, J = 9.2 Hz, 1H); 6.84 (t, J = 3.6 Hz, 1H); 4.03 (m, 2H); 4.01 (m, 2H); 2.01 (s, 6H); 1.66 (s, 6H).    0.01 0.007 587

491.2(M + 1)    0.01 0.012 588

454.2(M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.73- 7.70 (m, 2H); 7.21 (t, J = 8.8 Hz, 2H); 6.87 (t, J = 8.8 Hz, 1H); 6.68 (m, 1H); 4.12 (m, 4H); 2.17 (s, 3H); 2.15 (s, 6H); 1.76 (s, 6H).    0.01 0.004 589

470.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.62- 7.59 (m, 2H); 7.16-7.06 (m, 3H); 6.66 (d, J = 2.4 Hz, 1H); 6.50 (dd, J = 2.8 Hz, J = 8.4 Hz, 1H); 3.99 (m, 4H); 2.17 (s, 3H); 2.01 (s, 6H); 1.65 (s, 6H).    0.01 0.006 590

461.2(M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.32- 7.59 (m, 2H); 7.14 (m, 3H); 6.97 (m, 2H); 4.01 (m, 4H); 2.29 (s, 3H); 2.02 (s, 6H); 1.81 (s, 6H).    0.03 0.018 591

481.0(M + 1)    0.06 0.046 592

451.2(M + 1)    6.01 5.256 593

436.2(M + 1)    5.06 3.937 594

408.2(M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.58- 7.40 (m, 3H); 7.13 (t, J = 8.4 Hz, 1H); 6.99 (m, 2H); 6.61 (d, J = 8.0 Hz, 2H); 5.17-5.14 (m, 2H); 4.28- 3.92 (m, 4H); 2.20 (s, 3H), 1.70 (s, 3H), 1.65 (s, 3H).    0.02 0.032 595

460.2(M + 1)    0.34 0.485 596

432.2(M + 1)    0.03 0.029 597

432.2(M + 1)    0.03 0.024 598

383.2(M + 1)    0.04 0.074 599

499.3(M + 1)    0.12 0.134 600

412.2 (M + 1) ¹H-NMR (400 MHz, MeOH-d₄) δ 7.76 (dd, J = 5.2 Hz, J = 8.8 Hz, 2H); 7.29 (t, J = 8.4 Hz, 2H); 4.26 (s, 2H); 4.16 (s, 2H); 4.00 (s, 2H); 3.76 (s, 3H); 1.92 (s, 6H); 2.14 (s, 6H).    0.07 0.05 601

412.2 (M + 1)    3.96 4.117 602

460.2(M + 1)    0.17 0.204 603

383.2(M + 1)    0.05 0.073 604

399.2(M + 1)    0.04 0.049 605

403.0 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ 7.43 (td, J = 8.0 Hz, J = 1.0 Hz 1H); 7.38-7.34 (m, 1H); 7.24-7.18 (m, 1H); 7.11 (t, J = 8.40 Hz, 1H); 6.87-6.8 (m, 1 H); 6.37 (dd, J = 11.2 Hz, J = 2.40 Hz 1H); 6.33- 6.30 (m, 1H); 4.33 (s, 2H), 1.62 (s, 6H).    0.04 0.057 606

369.1 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.63- 7.59 (m, 2H); 7.11 (t, J = 8.40 Hz, 2H); 6.85 (t, J = 8.40 Hz, 2H); 6.7-6.68 (m, 2H); 4.3 (m, 2H); 3.87 (m, 2H); 3.01(s, 3H); 1.97 (s, 6H).    0.02 0.028 607

385.2(M + 1)    0.03 0.048 608

385.1(M + 1)    6.91 5.562 609

403.2(M + 1)    7.02 4.929 610

399.1(M + 1)    6.25 4.903 611

387.1(M + 1)    7.67 5.762 612

390.2(M + 1)    6.9 6.082 613

523.2(M + 1)    6.27 5.711 614

519.2(M + 1)    5.02 4.524 615

417.0(M + 1)    6.41 5.609 616

413.2(M + 1)    5.72 4.562 617

397.2(M + 1)    6.33 6.878 618

403.8(M + 1)    2.13 2.887 619

399.2(M + 1)    0.57 0.713 620

428.0 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.48- 7.41 (m, 3H); 7.16-7.14 (m, 3H); 6.71 (d, J = 8.4 Hz, 2H); 5.17-5.14 (m, 2H); 4.28-3.92 (m, 4H); 1.71 (s, 3H), 1.66 (s, 3H).    0.04 0.041 621

412.2(M + 1)    0.04 0.045 622

430.2(M + 1)    0.1 0.121 623

446.2(M + 1)    0.03 0.032 624

446.2(M + 1)    0.1 0.167 625

426.2(M + 1)    0.17 0.194 626

442.0 (M + 1) ¹H-NMR: (MeOH-d₄, 400 Hz) δ7.47- 7.39 (m, 2H); 7.19-7.11 (m, 2H); 6.67 (s, 1H); 6.52 (d, J = 8.0 Hz, 1H); 5.15 (s, 2H); 4.27-3.91 (m, 2H); 2.24 (s, 3H), 1.71 (s, 3H), 1.65 (s, 3H).    0.02 0.017 627

403.2(M + 1)    0.17 0.194 628

426.2 (M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.69- 7.73 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 6.87 (t, J = 8.8 Hz, 2H), 6.62-6.63 (m, 1H), 6.51-6.55 (m, 1H), 5.12 (s, 2H), 4.21 (t, J = 4.8 Hz, 2H), 4.02 (t, J = 4.8 Hz, 2H), 2.17 (s, 3H), 1.75 (s, 6H)    0.033 0.04 629

442.1 (M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.70- 7.73 (m, 2H), 7.22 (t, J = 8.0 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 6.77 (s, 1H), 6.62 (d, J = 6.0 Hz, 1H), 5.20 (s, 2H), 4.27 (s, 2H), 4.08 (s, 2H), 2.27 (s, 3H), 1.78 (s, 6H)    0.017 0.023 630

433.3 (M + 1)    0.035 0.085 631

426.3 (M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.72- 7.76 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 7.06 (t, J = 8.8 Hz, 1H), 8.56 (s, 1H), 6.53-6.54 (m, 1H), 5.20 (s, 2H), 4.27 (t, J = 4.8 Hz, 2H), 4.09 (t, J = 4.8 Hz, 2H), 2.13 (s, 3H), 1.79 (s, 6H)    0.049 0.062 632

442.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.71- 7.74 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 2.4, 8.4 Hz, 1H), 5.20 (s, 2H), 4.27 (t, J = 4.2 Hz, 2H), 4.09 (t, J = 4.2 Hz, 2H), 2.24 (s, 3H), 1.78 (s, 6H)    0.015 0.016 633

496.1(M + 1)    0.528 0.331 634

480.1(M + 1)    0.467 0.447 635

487.1(M + 1)    0.94 1.758 636

437.2(M + 1)    0.21 0.183 637

422.3 (M + 1)    0.027 0.026 638

408.3(M + 1)    0.065 0.068 639

428.2(M + 1)    0.082 0.093 640

478.2(M + 1)    3.95 4.51 641

422.2(M + 1)    0.799 1.285 642

460.2(M + 1)    2.01 2.497 643

478.2(M + 1)    2.798 2.171 644

462.1(M + 1)    0.31 0.49 645

426.1(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.75- 7.78 (m, 2H), 6.95-7.01 (m, 3H), 6.44-6.50 (m, 1H), 6.32- 6.36 (m, 1H), 4.19 (dd, J = 1.6, 6.8 Hz, 2H), 4.00 (dd, J = 1.6, 6.8 Hz, 2H), 1.47 (s, 6H)    5.13 7.6 646

428.1 (M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.59- 7.63 (m, 2H), 7.09 (t, J = 6.4 Hz, 2H), 6.95-7.02 (m, 1H), 6.46-6.52 (m, 1H), 6.34- 6.38 (m, 1H), 5.92 (s, 1H), 4.33 (dd, J = 4.4 , 14 Hz, 1H), 3.96 (dd, J = 4.8, 13.2 Hz, 1H), 3.70-3.78 (m, 1H), 3.46-3.54 (m, 1H), 1.73 (s, 3H), 1.36 (s, 3H)    5.68 6.13 647

470.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.72- 7.76 (m, 2H), 7.50-7.54 (m, 4H), 7.39 (t, J = 8.0 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.07-4.10 (m, 4H), 3.84 (t, J = 4.8 Hz, 2H), 2.09 (s, 6H)    0.279 0.25 648

422.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.76- 7.71 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 4.05-4.08 (m, 4H), 3.83-3.85 (m, 2H), 2.55 (q, J = 7.6 Hz, 2H), 2.09 (s, 6H), 1.18 (t, J = 7.6 Hz, 3H)    0.009 0.008 649

478.1(M + 1)    0.024 0.018 650

478.1(M + 1)    0.012 0.009 651

428.1(M + 1)    0.008 0.005 652

462.1(M + 1)    0.019 0.012 653

419.1(M + 1)    0.006 0.009 654

422.2(M + 1)    0.005 0.006 655

487.1(M + 1)    0.017 0.02 656

422.1(M + 1)    0.006 0.007 657

480.1(M + 1)    0.618 1.086 658

496.0(M + 1)    0.005 0.006 659

442.6(M + 1)    4.39 5.28 660

436.1(M + 1)    0.003 0.006 661

476.2(M + 1)    0.339 0.52 662

468.1(M + 1)    0.038 0.033 663

456.2(M + 1)    1.062 1.658 664

414.2(M + 1)    3.69 4.08 665

414.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.71- 7.74 (m, 2H), 7.29 (t, J = 8.8 Hz, 2H), 4.20 (t, J = 4.8 Hz, 2H), 4.12 (s, 2H), 3.86 (t, J = 4.8 Hz, 2H), 3.02- 3.09 (m, 1H), 2.02 (s, 6H), 1.79-1.86 (m, 2H), 1.57- 1.63 (m, 2H), 1.48-1.52 (m, 4H), 1.39-1.46 (m, 2H), 1.21-1.30 (m, 2H)    0.102 0.069 666

442.2(M + 1) >10 4.97 667

412.2(M + 1)    0.104 0.082 668

415.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.59- 7.63 (m, 2H), 7.32 (t, J = 8.8 Hz, 2H), 4.25 (d, J = 4.8 Hz, 2H), 4.13 (s, 2H), 3.97-4.04 (m, 1H), 3.88 (d, J = 4.8 Hz, 2H), 3.49-3.54 (m, 1H), 3.41- 3.47 (m, 2H), 3.25-3.30 (m, 1H), 2.92 (s, 6H), 2.45-2.53 (m, 1H), 2.23-2.28 (m, 1H), 2.01 (s, 6H)    3.43 >10 669

469.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.47- 7.51 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.13 (t, J = 4.4 Hz, 2H), 4.03 (s, 2H), 3.42 (d, J = 11.6 Hz, 2H), 3.15 (d, J = 12.4 Hz, 2H), 2.90 (dd, J = 10.8, 22.4 Hz, 4H), 2.00- 2.03 (m, 2H), 1.90 (s, 6H), 1.68-1.87 (m, 6H), 1.37- 1.47(m, 1H    3.98 >10 670

386.6(M + 1)    0.402 0.711 671

372.3(M + 1)    1.286 1.087 672

402.3(M + 1)    9.84 7.14 673

   8.87 >8.72 674

   6.28 6.31 675

446.5(M + 1)    0.014 0.021 676

415.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.59- 7.63 (m, 2H), 7.32 (t, J = 8.8 Hz, 2H), 4.25 (d, J = 4.8 Hz, 2H), 4.13 (s, 2H), 3.97-4.04 (m, 1H), 3.88 (d, J = 4.8 Hz, 2H), 3.49-3.54 (m, 1H), 3.41- 3.47 (m, 2H), 3.25-3.30 (m, 1H), 2.92 (s, 6H), 2.45-2.53 (m, 1H), 2.23-2.28 (m, 1H), 2.01 (s, 6H)    0.032 0.031 677

469.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.47- 7.51 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.13 (t, J = 4.4 Hz, 2H), 4.03 (s, 2H), 3.42 (d, J = 11.6 Hz, 2H), 3.15 (d, J = 12.4 Hz, 2H), 2.90 (dd, J = 10.8, 22.4 Hz, 4H), 2.00- 2.03 (m, 2H), 1.90 (s, 6H), 1.68-1.87 (m, 6H), 1.37- 1.47(m, 1H    0.08 0.076 678

415.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.59- 7.63 (m, 2H), 7.32 (t, J = 8.8 Hz, 2H), 4.25 (d, J = 4.8 Hz, 2H), 4.13 (s, 2H), 3.97-4.04 (m, 1H), 3.88 (d, J = 4.8 Hz, 2H), 3.49-3.54 (m, 1H), 3.41-3.47 (m, 2H), 3.25-3.30 (m, 1H), 2.92 (s, 6H), 2.45-2.53 (m, 1H), 2.23-2.28 (m, 1H), 2.01 (s, 6H)    0.053 0.047 679

469.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.47- 7.51 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.13 (t, J = 4.4 Hz, 2H), 4.03 (s, 2H), 3.42 (d, J = 11.6 Hz, 2H), 3.15 (d, J = 12.4 Hz, 2H), 2.90 (dd, J = 10.8, 22.4 Hz, 4H), 2.00- 2.03 (m, 2H), 1.90 (s, 6H), 1.68-1.87 (m, 6H), 1.37- 1.47(m, 1H    0.173 0.153 680

415.7(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.59- 7.63 (m, 2H), 7.32 (t, J = 8.8 Hz, 2H), 4.25 (d, J = 4.8 Hz, 2H), 4.13 (s, 2H), 3.97-4.04 (m, 1H), 3.88 (d, J = 4.8 Hz, 2H), 3.49-3.54 (m, 1H), 3.41- 3.47 (m, 2H), 3.25-3.30 (m, 1H), 2.92 (s, 6H), 2.45-2.53 (m, 1H), 2.23-2.28 (m, 1H), 2.01 (s, 6H)    0.085 0.173 681

454.1(M + 1)    0.272 0.196 682

470.1(M + 1)    0.124 0.111 683

454.1(M + 1)    0.125 0.112 684

470.1(M + 1)    0.03 0.017 685

474.1(M + 1)    0.173 0.131 686

452.2(M + 1)    0.628 0.524 687

412.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.70- 7.74 (m, 2H), 7.21 (t, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 6.62 (s, 1H), 6.50 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 4.25 (s, 2H), 4.07 (s, 2H), 1.77 (s, 6H)    3.42 (NF54) 3.35 688

413.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.67- 7.71 (m, 2H), 7.15-7.21 (m, 2H), 6.92-6.97 (m, 2H), 6.71-6.76 (m, 2H), 4.57- 4.63 (dm, 1H), 3.76-3.79 (m, 1H), 3.68-3.70 (m, 1H), 1.91 (s, 3H), 1.84 (s, 3H)    0.106 (NF54) 0.134 689

440.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.33- 7.42 (m, 3H), 7.06-7.08 (m, 1H), 6.70 (t, J = 9.2 Hz, 2H), 6.69-6.71 (m, 1H), 6.58- 6.62 (m, 1H), 4.38 (s, 2H), 3.66 (t, J = 8.0 Hz, 2H), 2.89 (t, J = 8.0 Hz, 2H), 2.25 (d, J = 1.6 Hz, 3H), 1.88-1.95 (m, 2H), 1.77 (s, 6H)    0.512 0.295 690

441.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.51- 7.54 (m, 1H), 7.44-7.48 (m, 1H), 7.37-7.42 (m, 1H), 7.05-7.12 (m, 1H), 6.86 (dt, J = 1.6, 9.2 Hz, 1H), 6.57- 6.61 (m, 1H), 6.47-6.53 (m, 1H), 4.58 (d, J = 2.0 Hz, 2H), 3.91 (t, J = 6.0 Hz, 1H), 3.64- 3.72 (m, 3H), 3.36 (s, 3H), 2.17 (d, J = 1.2 Hz, 2H), 1.91 (s, 3H), 1.89 (s, 3H)    0.866 0.76 691

455.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.37- 7.43 (m, 2H), 7.31-7.34 (m, 1H), 7.06-7.11 (m, 1H), 6.97 (t, J = 8.8 Hz, 1H), 6.71-6.73 (m, 1H), 6.58-6.62 (m, 1H), 4.39 (s, 2H), 3.62-3.65 (m, 2H), 3.36 (br, 5H), 3.34 (s, 1H), 3.26 (s, 3H), 2.24 (d, J = 2.0 Hz, 3H), 1.79 (s, 6H)    0.068 0.06 692

469.2(M + 1)    6.45 5.34 693

411.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.58- 7.62 (m, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (dd, J = 5.6, 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.23 (s, 2H), 4.06-4.09 (m, 4H), 3.83 (d, J = 5.6 Hz, 2H), 2.05 (s, 6H)    0.008 0.008 694

407.3(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.59- 7.62 (m, 2H), 7.29 (t, J = 8.4 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 4.19 (s, 2H), 4.04-4.08 (m, 4H), 3.80 (t, J = 4.8 Hz, 2H), 2.31 (s, 3H), 2.04 (s, 6H)    0.011 0.007 695

423.1(M + 1)    0.017 0.019 696

429.2(M + 1)    0.02 0.022 697

411.1(M + 1)    0.362 0.256 698

415.3(M + 1)    8.81 9.02 699

399.3(M + 1)    0.678 (NF54) ND 700

407.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.73- 7.77 (m, 3H), 7.21-7.30 (m, 6H), 4.82-4.86 (m, 1H), 4.13- 4.18 (m, 2H), 4.61 (s, 1H), 3.71-3.77 (m, 1H), 3.53- 3.58 (m, 1H), 3.09-3.21 (m,  >9.51 7.0 1H), 2.34 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H) 701

425.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.76- 7.79 (m, 3H), 7.32-7.38 (m, 1H), 7.28 (t, J = 8.8 Hz, 2H), 7.11 (d, J = 4.0 Hz, 1H), 7.06 (dt, J = 10, 2.4 Hz, 1H), 6.99 (dt, J = 2.8, 8.4 Hz, 1H), 4.62 (t, J = 6.4 Hz, 1H), 4.35    8.27 7.35 (t, J = 4.8 Hz, 2H), 3.84-3.98 (m, 2H), 2.79-2.87 (m, 2H), 2.14-2.20 (m, 2H), 2.04 (s, 3H), 2.03 (s, 3H) 702

441.2(M + 1)    6.03 5.85 703

399.3(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.81 (s, 1H), 7.76-7.80 (m, 2H), 7.29 (t, J = 8.8 Hz, 2H), 4.60- 4.64 (m, 2H), 4.40-4.43 (m, 2H), 3.92-3.95 (m, 2H), 2.05 (s, 3H), 2.04 (s, 3H), 1.70-    8.57 8.29 1.83 (m, 6H), 1.49-1.53 (m, 1H), 1.20-1.42 (m, 4H), 0.99- 1.35 (m, 2H) 704

393.3(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.42- 7.46 (m, 2H), 7.31-7.39 (m, 4H), 7.13 (t, J = 8.8 Hz, 2H), 4.09-4.12 (m, 4H), 3.82 (t, J = 4.8 Hz, 2H), 2.42 (s, 3H), 2.08 (s, 6H)    0.236 0.232 705

397.3(M + 1)    1.241 0.76 706

431.2(M + 1)    0.252 0.237 707

383.1(M + 1)    6.54 >10 708

440.1(M + 1)    0.809 1.134 709

413.1(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.67- 7.71 (m, 2H), 7.09-7.17 (m, 6H), 4.06 (s, 2H), 4.02 (t, J = 4.8 Hz, 2H), 3.80 (t, J = 4.8 Hz, 2H), 2.04 (s, 6H)    0.003 0.008 710

429.1(M + 1)    0.028 (NF54) ND 711

431.1(M + 1)    0.034 (NF54) ND 712

427.2(M + 1)    0.019 (NF54) ND 713

425.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.83- 7.87 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.11 (t, J = 4.4 Hz, 2H), 3.98 (s, 2H), 3.83 (t, J = 4.4 Hz, 2H), 2.29 (s, 3H), 1.98 (s, 6H)    0.008 ND 714

429.2(M + 1)    0.007 0.004 715

429.1(M + 1)    0.006 0.006 716

445.1(M + 1)    0.002 0.001 717

439.2(M + 1)    0.026 0.016 718

447.1(M + 1)    0.008 0.006 719

445.1(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.58- 7.62 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.14 (t, J = 8.4 Hz, 2H), 6.89 (s, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.09 (s, 2H), 4.17 (s, 2H), 3.99 (s, 2H), 1.67 (s, 6H)    0.481 0.361 720

445.1(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.60- 7.63 (m, 2H), 7.11 (t, J = 8.4 Hz, 2H), 6.75-6.80 (m, 1H), 6.59 (d, J = 4.8 Hz, 1H), 6.50 (br, 1H), 5.09 (s, 2H), 4.16 (s, 2H), 3.97 (s, 2H), 2.07 (s, 3H), 1.67 (s, 6H)    0.07 0.069 721

441.0(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.78- 7.82 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.8 Hz, 2H), 4.61-4.65 (m, 1H), 4.08 (s, 2H), 3.77-3.92 (m, 3H), 2.43 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H)    0.042 ND 722

455.1(M + 1)    0.381 0.281 723

463.1(M + 1)    0.089 0.068 724

461.1(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.70- 7.74 (m, 2H), 7.21 (t, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 6.62 (s, 1H), 6.50 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 4.25 (s, 2H), 4.07 (s, 2H), 1.77 (s, 6H)    0.509 0.287 725

457.1    5.21 (NF54) ND 726

544.3(M + 1)    1.925 1.48 727

634.3(M + 1)    6.56 2.969 728

615.3(M + 1)    5.4 1.485 729

705.3(M + 1) >10 6.29 730

601.2(M + 1)    1.365 0.474 731

734.2(M + 1)    2.27 (NF54) 5.61 732

905.4(M + 1)    1.223 (NF54) 1.438 737

305.2(M + 1) ¹H NMR (400 MHz, CDCl₃): δ 9.27 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 3.2 Hz, 1H), 7.79 (t, J = 3.2 Hz, 1H), 7.33 (br, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 3.87 (s, 2H), 3.14 (s, 2H), 2.22 (s, 3H), 2.02 (s, 4H)    7.85 4.09 738

328.5(M + 1)    3.24 1.555 739

412.6(M + 1)    0.768 0.881 740

367.2(M + 1)    9.33 8.73 741

404.6(M + 1)    5.25 4.83 742

388.2(M + 1)    6.43 11.6 743

401.2(M + 1)    2.675 3.003 744

437.6(M + 1)    5.24 2.813 745

390.2(M + 1)    3.57 4.23 746

382.2(M + 1) >10 6.94 747

388.2(M + 1)    2.234 4.48 748

332.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 8.09 (s, 1H), 7.75-7.79 (m, 4H), 7.17 (t, J = 8.8 Hz, 2H), 6.93(d, J = 8.0 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 2.35 (s, 3H), 2.14 (s, 3H)    3.44 4.15 749

360.8(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.64- 7.67 (m, 2H), 7.20-7.29 (m, 3H), 6.64 (dd, J = 2.8, 11.2 Hz, 1H), 6.55-6.58 (m, 1H), 3.90 (t, J = 5.6 Hz, 2H), 3.11 (t, J = 5.6 Hz, 2H), 2.05-2.12 (m, 4H)    1.053 0.814 750

322.2(M + 1)    4.77 4.96 751

318.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 8.39 (d, J = 6.8 Hz, 1H), 7.89- 8.02 (m, 4H), 7.47(dt, J = 1.2, 6.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 2.24(s, 3H)    1.792 4.55 752

370.8(M + 1)    1.619 2.381 753

336.2(M + 1) ¹H NMR (400 MHz, CD₃OD): δ 7.65- 7.68 (m, 2H), 7.19 (t, J = 8.8 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.62(dd, J = 2.0, 6.4 Hz, 1H), 4.00-4.05 (m, 1H), 3.35- 3.38 (m, 1H), 3.17-3.24 (m, 1H), 3.05-3.14 (m, 1H), 2.24(s, 3H), 2.12-2.21 (m, 2H), 1.67-1.77 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H)    0.376 0.592 754

374.8(M + 1)    0.104 0.19

Assays

Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of parasitemia in infected red blood cells. The proliferation is quantified by the addition of SYBR Green I (INVITROGEN)® dye which has a high affinity for double stranded DNA.

The following assay illustrates the invention without in any way limiting the scope of the invention. This parasite proliferation assay measures the increase in parasite DNA content using a DNA intercalating dye, SYBR Green®.

3D7 P. falciparum strain is grown in complete culturing media until parasitemia reaches 3% to 8% with O+ human erythrocytes. 20 μl of screening media is dispensed into 384 well assay plates. 50 nl of compounds of the invention (in DMSO), including antimalarial controls (mefloquine, pyrimethamine and artemisinin), are then transferred into the assay plates, as well as DMSO alone to serve as a negative control for inhibition. Then 30 μl of a suspension of a 3D7 P. falciparum infected erythrocytes in screening media is dispensed into the assay plates such that the final hematocrit is 2.5% with a final parasitemia of 0.3%. The plates are placed in a 37° C. incubator for 72 hours in a low oxygen environment containing 93% N₂, 4% CO₂, and 3% O₂ gas mixture. 10 μl of lysis buffer (saponin, triton-X, EDTA) containing a 10× solution of SYBR Green I® in RPMI media is dispensed into the plates. The plates are lidded and kept at room temperature overnight for the lysis of the infected red blood cells. The fluorescence intensity is measured (excitation 425 nm, emission 530 nm) using the Envision™ system (Perkin Elmer). The percentage inhibition of 50%, EC₅₀, is calculated for each compound.

Compounds of the invention have an EC₅₀ of 10 μM or less, preferably less than 1 μM, 750 nM, 500 nM 400 nM, 300 nM, 200 nM, 100 nM and 50 nM. Compounds of the invention can significantly delay the increase in parasitemia.

Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of kinetoplastid parasite Trypanosoma brucei. The proliferation is quantified by the addition of Cell Titer Glo (Promega®) a luminescent cell viability assay that measures the number of viable cells in culture based on the quantification of cellular ATP amount, which is an indicator of metabolically active cells.

The following assay illustrates the invention without in any way limiting the scope of the invention. This parasite proliferation assay measures the increase in parasite growth using an assay that measures ATP activity, Cell Titer Glo®.

Trypanosoma brucei Lister 427 strain is grown in HMI-9 Trypanosome media for T. brucei bloodstream form. 30 μl of HMI-9 media is dispensed into 384 well assay plates. 200 nl of compounds of the invention (in DMSO), including anti-trypanosome controls (Pentamidine and suramin), are then transferred into the assay plates, as well as DMSO alone to serve as a negative control for inhibition. Then 25 μl of a suspension of T. brucei culture in HMI-9 media is dispensed into the assay plates. The final concentration of parasites in culture corresponds to 1.7% of 0.5 uM ATP activity with Cell Titer Glo® in HMI-9 media. The plates are placed in a 37° C. incubator for 48 hours in an atmospheric environment containing 5% CO₂. 40 μl of Cell Titer Glo® is dispensed into the plates. The plates are then read for luminescence. The percentage inhibition of 50%, EC₅₀, is calculated for each compound.

Compounds of the invention have an EC₅₀ of 10 μM or less, preferably less than 1 μM, 750 nM, 500 nM 400 nM, 300 nM, 200 nM, 100 nM and 50 nM. Compounds of the invention can significantly delay the proliferation of T. brucei. For example, 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone (example 412) and 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one (Example 29) have an EC₅₀ of 10 μM and 7 μM, respectively.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes. 

1. A compound of Formula Ib:

in which: R_(b) is selected from hydrogen and C₁₋₄alkyl; R₄ is selected from hydrogen and C₁₋₆alkyl; R₅ is selected from hydrogen and C₁₋₆alkyl; or R₄ and R₅ together with the carbon atom to which R₄ and R₅ are attached forms C₃₋₈cycloalkyl; R₆ is selected from C₆₋₁₀aryl, C₃₋₈cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said aryl or heterocyclic of R₆ is optionally substituted by 1 to 3 radicals independently selected from halo, hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy; R₇ is selected from hydrogen and C₁₋₃alkyl; R₈ is selected from C₁₋₁₀alkyl, C₆₋₁₀aryl-C₀₋₄alkyl, C₃₋₈cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said aryl or heterocyclic of R₈ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, hydroxy, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, C₁₋₆alkoxy, —C(O)OR₁₈, —S(O)₀₋₂R₁₈, —C(O)NHR₁₈, —NHS(O)₀₋₂R₁₈, phenyl and a saturated, unsaturated or partially unsaturated 5-6 member heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR₃₀, S(O)₀₋₂ and O; wherein R₃₀ is selected from hydrogen and C₁₋₆alkyl; wherein said aryl or heterocyclic substituent of R₈ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, hydroxy, C₁₋₆alkyl and halo-substituted-C₁₋₆alkyl; wherein R₁₈ is selected from hydrogen and C₁₋₆alkyl; R₉ is selected from hydrogen and C₁₋₆alkyl; R₁₀ is selected from hydrogen and C₁₋₆alkyl; R₁₁ is selected from hydrogen and C₁₋₆alkyl; R₁₂ is selected from hydrogen and C₁₋₆alkyl; or R₁₁ and R₁₂ combine to form C(O); or the pharmaceutically acceptable salts thereof.
 2. (canceled)
 3. The compound of claim 1 in which: R₄, R₅, R₉ and R₁₀ are independently selected from hydrogen and methyl; and R₁₁ and R₁₂ are both hydrogen; or R₁₁ and R₁₂ combine to form C(O).
 4. The compound of claim 3 in which: R₆ is selected from phenyl, cyclohexyl and pyridinyl; wherein said phenyl or pyridinyl of R₆ is optionally substituted by 1 to 3 radicals independently selected from halo, pentyl, hydroxy, methyl and methoxy.
 5. The compound of claim 4 in which: R₇ is selected from hydrogen, methyl, ethyl and isopropyl; and R₈ is selected from phenyl, benzyl, benzo[d][1,3]dioxol-5-yl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl and pyrazolyl; wherein said phenyl, benzyl, benzo[d][1,3]dioxol-5-yl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl or pyrazolyl of R₈ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, trifluoromethoxy, dimethyl-amino, difluoromethoxy, carboxy, methoxy-carbonyl, methyl-sulfonyl-amino, methyl-sulfonyl, methyl-amino-carbonyl, phenyl, piperidinyl, piperidinyl-methyl, piperazinyl and piperazinyl-methyl. 6-7. (canceled)
 8. The compound of claim 1 selected from: N,2-bis(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(cyclopropylamino)-1-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]ethan-1-one; N-[4-({2-[2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl]-2-oxoethyl}amino)butyl]acetamide; 2-(3-fluorophenyl)-N-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 4-{[2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; N-(4-chlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(3-methylphenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(3,4-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(3-chlorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(2,4-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (5R,8R)-2,8-dibenzyl-3-methyl-5-(2-phenylethyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-tert-butyl-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-6-methyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(2,5-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-methylphenyl)-2-(pyridin-4-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-N-ethyl-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-8,8-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 4-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-fluorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-ethyl-N-(3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N,2-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluoro-3-methylphenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(3-chloro-4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-chloro-3-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-8,8-dimethyl-3-{[3-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(3-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3,4-dichlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 4-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N-(3-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; no carbonyl 2-(4-fluorophenyl)-8,8-dimethyl-N-[3-(trifluoromethyl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; no carbonyl 2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzoic acid; 2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H, 8H-imidazo[1,2-a]pyrazin-3-yl]2amino}benzonitrile; 5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzoic acid; 5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 5-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; N,2-bis(4-fluorophenyl)-5,5,7,8,8-pentamethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 2-(4-fluorophenyl)-5,5,7,8,8-pentamethyl-3 [(4-methylphenyl)amino]5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-5,5,7,8,8-pentamethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-fluoro-4-methylphenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3-chloro-4-methylphenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-8,8-dimethyl-3-[(3,4,5-trifluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(6-methoxypyridin-3-yl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylpyridin-2-yl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-chloro-4-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; (8R)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(3,4-difluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-N-(3,4,5-trifluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; (8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8S)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; (8R)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-(quinolin-3-ylamino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-3-[(4-methanesulfonylphenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-3-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 2-(4-fluorophenyl)-8,8-dimethyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-(4-fluorophenyl)-6,6-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N,2-bis(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 2-fluoro-5-{[2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile; 3-[(3-fluoro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-fluoro-4-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(3-chloro-4-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N,2-bis(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chlorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(4-chloro-3-methylphenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; 5-{[2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; 3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-7,8,8-trimethyl-5H, 6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine; N,2-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-[1,2a]pyrazine-3-carboxamide. 9-10. (canceled)
 11. A method for preventing or treating a Plasmodium related disease in a subject, comprising administering to a subject a therapeutically effective amount of a compound of claim 1 and optionally in combination with one or more therapeutic agents.
 12. The method of claim 11 wherein the Plasmodium related disease is malaria.
 13. The method of claim 11, wherein the contacting occurs in vitro or in vivo.
 14. The method of claim 11, wherein the one or more therapeutic agents are selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.
 15. The method of claim 14 wherein the anti-malarial drug is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, and pyronaridine.
 16. The method of claim 15, wherein the compound of claim 1 is administered prior to, simultaneously with, or after the one or more therapeutic agents.
 17. The method of claim 11, wherein said subject is a human. 